病毒进化及病毒和宿主作物之间相互作用的研究
摘要
病毒进化及突变模式,病毒和作物之间相互作用的机理越来越受到作物学家们的关注。在这篇论文中,作者尝试在微观尺度下,利用生物信息学和分子力学工具揭示蛋白质的动态结构及相关重要的生物功能。本研究探讨了在RNA干涉中Argonaute蛋白识别小RNA和分解mRNA的机理,计算了病毒蛋白和宿主RNA的相互结合能。同时利用交互信息模型,发展了基于位点转换的流感病毒进化网络。整个工作主要分为下面三个部分。
在第一部分,作者利用分子动力学模拟(MD)来研究p19蛋白和siRNA的识别机制及其突变体的效应。研究的对象包括野生型和W39G&W42G突变体。常规MD和拉伸分子动力学(SMD)都表明当p19与小RNA结合时,突变型要比野生型不稳定。这些结果和实验的结果是一致的。与此同时,作者用自由能微扰(FEP)成功预测了p19和RNA结合自由能的变化,相对于野生型,单氨基酸突变体(W39G)损失了6.98±0.95kcal/mol的结合自由能,双氨基酸突变W39/42G损失了12.8±1.0kcal/mol的结合自由能,并且得出90%的贡献来自范德华力相互作用。这些结果表明W39/42G突变打断了RNA碱基和色氨酸(tryptophan)之间π-π键相互作用。这些大规模的模拟提供了RNA病毒蛋白和其宿主键协同进化关系的新见解。
在第二部分,作者揭示了Argonaute二聚体识别和降解mRNA的机制并建立了两种最近报道的靶链RNA (11-nt和15-nt)和Argonaute三聚体的三维结构模型。对于两个不同长度的靶RNA链,我们得出了相似的模拟结果：当碱基错配个数在引导链(guide) RNA和靶链(target) RNA的"seed"位置之间增加时,A-form结构的双螺旋会逐渐变形,当碱基错配个数超过两个时,Argonaute三聚体将不能稳定存在。在极端的4个碱基错配情况下,核苷酸双链与Argonaute的Ll和L2片段的氢键将全部断掉,由此诱发了整个PAZ功能域在空间上沿着Ll和L2片段的相对旋转,因而导致Argonaute蛋白整个核酸结合区被打开。这种在核酸和PAZ功能域之间的长距离的相互作用,揭示了"seed"区域在引导链-靶链结合中的重要作用：它不仅决定了引导链-靶链成核和延伸,而且控制了整个PAZ功能域的构象变化。除此以外,我们把引导链由DNA换成了更加普遍的RNA,并得出了相似的结论。这些结果支持了RNA也可能在Thermus thermophilus昀RNA干涉中作为引导链,并且对碱基错配不像DNA作为引导链那样敏感。
在最后一节,作者通过交互信息预型对流感病毒抗原性及其遗传进化途径进行了分析。交互信息模型作用于每一个hemagglutinin (HA)蛋白位点,从而生成位点转移网络(STN)。STN网络表明大部分的动态相互作用位置在抗原表位周围和受体结合域(RBD)地区,并且突变位点对将要突变成的氨基酸的种类有强烈的偏好。STN网络还表明,随着时间的推移,抗原的变化也在积累并当在多个抗原位点同时突变时,整个病毒的表型会发生较大的变化。通过聚类分析把整个STN互做网络分成若干个小的子网络揭示了更多具体的关于流感抗原的特征：子网路内部的位点和子网路之间连接的位点对于流感的抗原漂移是一样重要的。最后作者成功提出了基于STN网络的预测HA蛋白突变的5步模型。在对2003-2004季度突变位点预测中,该模型获得了70%的准确性。该模型还预测了最近的下一个可能的抗原漂移。同样,STN网络的结果和进化树分析以及实验结果均相吻合。
Capturing the evolution trend of virus and understanding the interaction between virus and its host plants are of great concern in crop science. In this thesis, the author tries to explain the fundamental biological processes in micro-scale by investigating corresponding protein dynamics structures using bioinformatics tools and molecular mechanics. The mechanism of how Argonaute protein recognize small RNAs and cleave target mRNA in RNA interference, as well as the binding affinity between virus protein p19and its host RNA are explored. The genetic evolution of influenza virus is mapped using the mutual information based site transition network. The entire work is divided by the following three sections.
In the first section, the p19-siRNA recognition mechanism and mutation effects were studied by molecular dynamics simulations of the wild-type and mutant p19protein (W39G&W42G) binding with a21-nt siRNA duplex. Simulations with standard molecular dynamics (MD) and steered molecular dynamics have shown that the double mutant structure is indeed much less stable than the wild-type, consistent with the recent experimental findings. The free energy perturbation successfully predicted a binding affinity loss of6.98±0.95kcal/mol for the single mutation W39G, and12.8±1.0kcal/mol loss for the double mutation W39/42G. with the van der Waals interactions dominating the contribution (-90%). These results indicate that the W39/42G mutations essentially destroy the important p19-siRNA recognition by breaking the strong stacking interaction between Cyt1and Gua'19with end-capping tryptophans. These large scale simulations might provide new insights into the interactions and co-evolution relationship between RNA virus proteins and their hosts.
The second section examined the recognition mechanism and cleavage activity of target mRNA by Argonaute silencing complexes. Both the recently reported11-nt and15-nt guide-target strands-Ago complexes are modeled. Our simulations show comparable results for both the11-and15-nt nucleic-acid strands, whose A-form-like helix duplex gradually distorts as the number of mismatches at the seed region increases and the complex can survive no more than two mismatches. In the extreme four-mismatch mutant complex, the hydrogen bonds between the nucleic-acid duplex and L1/L2segments of Ago protein are broken, which introduce a bending motion of the PAZ domain along the L1/L2"hinge-like" connection region and result in the opening of the nucleic-acid-binding channel. These long-range interactions between the seed region and PAZ domain, mediated by the L1/L2segments, reveals the central role of the seed region in the guide-target recognition-it not only determines the guide-target duplex's nucleation, and propagation, but also controls the dynamics of the large conformational changes in the PAZ domain. The catalytic activities of RNA guided mRNA cleavage are also investigated in our simulation by replacing the guide DNA by corresponding RNA strand in the Ago-DNA-mRNA complexes. Similar behaviors are found for the Ago-RNA-mRNA complexes, which support the hypothesis that small RNAs might also be used as the guide strand for Thermus thermophilus Ago-like proteins and may also have larger tolerance for the mismatches in the seed region.
In the final section, the antigenic and genetic evolution pathways of influenza virus is predicted by mutual information model. The mutual information method was used to design a site transition network (STN) for each amino acid site in the hemagglutinin (HA) sequence. The STN network indicates that most of the dynamic interactions are positioned around the epitopes and the RBD regions, with strong preferences in both the mutation sites and amino acid types being mutated to. The network also shows that antigenic changes accumulate over time, with occasional large changes due to multiple co-occurring mutations at antigenic sites. The cluster analysis by subdividing the STN into several subnetworks reveals a more detailed view about the features of the antigenic change:The characteristic inner sites and the connecting inter-subnetwork sites are both responsible for the drifts. A novel5-step prediction algorithm based on the STN shows a reasonable accuracy in reproducing historical HA mutations. For example, our method can reproduce the2003-2004A/H3N2mutations with～70%accuracy. The method also predicts seven possible mutations for the next antigenic drift in the coming season. The site transition network approach also agrees well with the phylogenetic tree and antigenic maps based on HA inhibition assays.
在第一部分,作者利用分子动力学模拟(MD)来研究p19蛋白和siRNA的识别机制及其突变体的效应。研究的对象包括野生型和W39G&W42G突变体。常规MD和拉伸分子动力学(SMD)都表明当p19与小RNA结合时,突变型要比野生型不稳定。这些结果和实验的结果是一致的。与此同时,作者用自由能微扰(FEP)成功预测了p19和RNA结合自由能的变化,相对于野生型,单氨基酸突变体(W39G)损失了6.98±0.95kcal/mol的结合自由能,双氨基酸突变W39/42G损失了12.8±1.0kcal/mol的结合自由能,并且得出90%的贡献来自范德华力相互作用。这些结果表明W39/42G突变打断了RNA碱基和色氨酸(tryptophan)之间π-π键相互作用。这些大规模的模拟提供了RNA病毒蛋白和其宿主键协同进化关系的新见解。
在第二部分,作者揭示了Argonaute二聚体识别和降解mRNA的机制并建立了两种最近报道的靶链RNA (11-nt和15-nt)和Argonaute三聚体的三维结构模型。对于两个不同长度的靶RNA链,我们得出了相似的模拟结果：当碱基错配个数在引导链(guide) RNA和靶链(target) RNA的"seed"位置之间增加时,A-form结构的双螺旋会逐渐变形,当碱基错配个数超过两个时,Argonaute三聚体将不能稳定存在。在极端的4个碱基错配情况下,核苷酸双链与Argonaute的Ll和L2片段的氢键将全部断掉,由此诱发了整个PAZ功能域在空间上沿着Ll和L2片段的相对旋转,因而导致Argonaute蛋白整个核酸结合区被打开。这种在核酸和PAZ功能域之间的长距离的相互作用,揭示了"seed"区域在引导链-靶链结合中的重要作用：它不仅决定了引导链-靶链成核和延伸,而且控制了整个PAZ功能域的构象变化。除此以外,我们把引导链由DNA换成了更加普遍的RNA,并得出了相似的结论。这些结果支持了RNA也可能在Thermus thermophilus昀RNA干涉中作为引导链,并且对碱基错配不像DNA作为引导链那样敏感。
在最后一节,作者通过交互信息预型对流感病毒抗原性及其遗传进化途径进行了分析。交互信息模型作用于每一个hemagglutinin (HA)蛋白位点,从而生成位点转移网络(STN)。STN网络表明大部分的动态相互作用位置在抗原表位周围和受体结合域(RBD)地区,并且突变位点对将要突变成的氨基酸的种类有强烈的偏好。STN网络还表明,随着时间的推移,抗原的变化也在积累并当在多个抗原位点同时突变时,整个病毒的表型会发生较大的变化。通过聚类分析把整个STN互做网络分成若干个小的子网络揭示了更多具体的关于流感抗原的特征：子网路内部的位点和子网路之间连接的位点对于流感的抗原漂移是一样重要的。最后作者成功提出了基于STN网络的预测HA蛋白突变的5步模型。在对2003-2004季度突变位点预测中,该模型获得了70%的准确性。该模型还预测了最近的下一个可能的抗原漂移。同样,STN网络的结果和进化树分析以及实验结果均相吻合。
Capturing the evolution trend of virus and understanding the interaction between virus and its host plants are of great concern in crop science. In this thesis, the author tries to explain the fundamental biological processes in micro-scale by investigating corresponding protein dynamics structures using bioinformatics tools and molecular mechanics. The mechanism of how Argonaute protein recognize small RNAs and cleave target mRNA in RNA interference, as well as the binding affinity between virus protein p19and its host RNA are explored. The genetic evolution of influenza virus is mapped using the mutual information based site transition network. The entire work is divided by the following three sections.
In the first section, the p19-siRNA recognition mechanism and mutation effects were studied by molecular dynamics simulations of the wild-type and mutant p19protein (W39G&W42G) binding with a21-nt siRNA duplex. Simulations with standard molecular dynamics (MD) and steered molecular dynamics have shown that the double mutant structure is indeed much less stable than the wild-type, consistent with the recent experimental findings. The free energy perturbation successfully predicted a binding affinity loss of6.98±0.95kcal/mol for the single mutation W39G, and12.8±1.0kcal/mol loss for the double mutation W39/42G. with the van der Waals interactions dominating the contribution (-90%). These results indicate that the W39/42G mutations essentially destroy the important p19-siRNA recognition by breaking the strong stacking interaction between Cyt1and Gua'19with end-capping tryptophans. These large scale simulations might provide new insights into the interactions and co-evolution relationship between RNA virus proteins and their hosts.
The second section examined the recognition mechanism and cleavage activity of target mRNA by Argonaute silencing complexes. Both the recently reported11-nt and15-nt guide-target strands-Ago complexes are modeled. Our simulations show comparable results for both the11-and15-nt nucleic-acid strands, whose A-form-like helix duplex gradually distorts as the number of mismatches at the seed region increases and the complex can survive no more than two mismatches. In the extreme four-mismatch mutant complex, the hydrogen bonds between the nucleic-acid duplex and L1/L2segments of Ago protein are broken, which introduce a bending motion of the PAZ domain along the L1/L2"hinge-like" connection region and result in the opening of the nucleic-acid-binding channel. These long-range interactions between the seed region and PAZ domain, mediated by the L1/L2segments, reveals the central role of the seed region in the guide-target recognition-it not only determines the guide-target duplex's nucleation, and propagation, but also controls the dynamics of the large conformational changes in the PAZ domain. The catalytic activities of RNA guided mRNA cleavage are also investigated in our simulation by replacing the guide DNA by corresponding RNA strand in the Ago-DNA-mRNA complexes. Similar behaviors are found for the Ago-RNA-mRNA complexes, which support the hypothesis that small RNAs might also be used as the guide strand for Thermus thermophilus Ago-like proteins and may also have larger tolerance for the mismatches in the seed region.
In the final section, the antigenic and genetic evolution pathways of influenza virus is predicted by mutual information model. The mutual information method was used to design a site transition network (STN) for each amino acid site in the hemagglutinin (HA) sequence. The STN network indicates that most of the dynamic interactions are positioned around the epitopes and the RBD regions, with strong preferences in both the mutation sites and amino acid types being mutated to. The network also shows that antigenic changes accumulate over time, with occasional large changes due to multiple co-occurring mutations at antigenic sites. The cluster analysis by subdividing the STN into several subnetworks reveals a more detailed view about the features of the antigenic change:The characteristic inner sites and the connecting inter-subnetwork sites are both responsible for the drifts. A novel5-step prediction algorithm based on the STN shows a reasonable accuracy in reproducing historical HA mutations. For example, our method can reproduce the2003-2004A/H3N2mutations with～70%accuracy. The method also predicts seven possible mutations for the next antigenic drift in the coming season. The site transition network approach also agrees well with the phylogenetic tree and antigenic maps based on HA inhibition assays.
引文
Agrawal, N., P. V. Dasaradhi, et al. (2003). "RNA interference:biology, mechanism, and applications." Microbiol Mol Biol Rev 67(4):657-685.
Ahlquist, P. (2002). "RNA-dependent RNA polymerases, viruses, and RNA silencing." Science 296(5571):1270-1273.
Alder, B. J. a. W., T. E. (1957). "Phase transition for a hard sphere system." J Chem Phvs 27:2.
Anandalakshmi R, G. J. Pruss, et al. (1998). "A viral suppressor of gene silencing in plants." Proc. Natl Acad. Sci. USA 95:13079-13084.
Aqvist, J. and A. Warshel (1989). "Energetics of ion permeation through membrane channels. Solvation of Na+by gramicidin A." Biophys J 56(1):171-182.
Bao Y., P. B., D. Dernovoy, B. Kiryutin, L. Zaslavsky, T. Tatusova, J. Ostell, and D. Lipman. (2008). "The influenza virus resource at the National Center for Biotechnology Information." J. Virol.82(2):596-601.
Baulcombe, D. (2002). "Viral suppression of systemic silencing." Trends Microbiol 10(7):306-308.
Baulcombe, D. (2004). "RNA silencing in plants." Nature 431:356-363.
Bernstein, E., A. A. Caudy, et al. (2001). "Role for a bidentate ribonuclease in the initiation step of RNA interference." Nature 409(6818):363-366.
Bird, A. (2002). "DNA methylation patterns and epigenetic memory." Genes Dev 16(1):6-21.
Boresch, S. and M. Karplus (1995). "The meaning of component analysis:decomposition of the free energy in terms of specific interactions." J Mol Biol 254(5):801-807.
Brady, G. P. and K. A. Sharp (1995). "Decomposition of interaction free energies in proteins and other complex systems." J Mol Biol 254(1):77-85.
Bren, M., J. Florian, et al. (2007). "Do all pieces make a whole? Thiele cumulants and the free energy decomposition." Theoretical Chemistry Accounts 117(4):535-540.
Brooks, B. R., C. L. Brooks,3rd, et al. (2009). "CHARMM:the biomolecular simulation program." J Comput Chem 30(10):1545-1614.
Brooks, B. R., R. E. Bruccoeri, et al. (1983). "CHARMM:A program for macromolecular energy, minimization, and dynamics calculations." J Comput Chem 4(2):187-217.
Brooks, C. L., M. Gruebele, et al. (1998). "Chemical physics of protein folding." Proc Natl Acad Sci U S A 95(19):11037-11038.
Brooks, C. L., J. N. Onuchic, et al. (2001). "Statistical thermodynamics-Taking a walk on a landscape." Science 293(5530):612-613.
Bush, R. M., C. A. Bender, et al. (1999). "Predicting the evolution of human influenza A.' Science 286(5446):1921-1925.
Bush, R. M., W. M. Fitch, et al. (1999). "Positive selection on the H3 hemagglutinin gene of human influenza virus A." Mol Biol Evol 16(11):1457-1465.
Butte, A. J. and I. S. Kohane (2000). "Mutual information relevance networks:functional genomic clustering using pairwise entropy measurements." Pacific Symposium on Biocomputing:418-429.
Butte, A. J., P. Tamayo, et al. (2000). "Discovering functional relationships between RNA expression and chemotherapeutic susceptibility using relevance networks." Proc Natl Acad Sci U S A 97(22):12182-12186.
Calabrese, J. M. and P. A. Sharp (2006). "Characterization of the short RNAs bound by the P19 suppressor of RNA silencing in mouse embryonic stem cells." Rna 12(12):2092-2102.
Chapman, E. J., A. I. Prokhnevsky, et al. (2004). "Viral RNA silencing suppressors inhibit the micro RNA pathway at an intermediate step." Gene Dev 18(10):1179-1186.
Chen, R. and E. C. Holmes (2006). "Avian influenza virus exhibits rapid evolutionary dynamics." Mol Biol Evol 23(12):2336-2341.
Chu, M, B. Desvoyes, et al. (2000). "Genetic dissection of tomato bushy stunt virus p19-protein-mediated host-dependent symptom induction and systemic invasion." Virology 266(1):79-87.
Cox, N. J. and K. Subbarao (2000). "Global epidemiology of influenza:past and present." Annu Rev Med 51:407-421.
Cramer, C. (2002). Essentials of Computational Chemistry., Chichester.
D. van der Spoel, E. Lindahl, et al. (2005). "Gromacs User Manual version 4.0." www.gromacs.org.
Das, P., J. Li, et al. (2009). "Free energy simulations reveal a double mutant avian H5N1 virus hemagglutinin with altered receptor binding specificity." J Comput Chem.
DeLano, W. L. (2008). "The PyMOL Molecular Graphics System." DeLano Scientific:San Carlos, CA, USA.
Deng, Y. and B. Roux (2006). "Calculation of standard binding free energies:aromatic molecules in the T4 lysozyme L99A mutant." J. Chem. Theo. Comp.2:1255-1273.
Deng, Y. Q. and B. Roux (2006). "Calculation of standard binding free energies:Aromatic molecules in the T4 lysozyme L99A mutant." Journal of Chemical Theory and Computation 2(5):1255-1273.
Desemo, M. and C. Holm (1998). "How to mesh up Ewald sums. Ⅰ. A theoretical and numerical comparison of various particle mesh routines." J Chem Phys 109(18):7678-7693.
Deserno, M. and C. Holm (1998). "How to mesh up Ewald sums. Ⅱ. An accurate error estimate for the particle-particle-particle-mesh algorithm." J Chem Phys 109(18):7694-7701.
Du, X., Z. Wang, et al. (2008). "Networks of genomic co-occurrence capture characteristics of human influenza A (H3N2) evolution." Genome Res 18(1):178-187.
Dunoyer, P., C. H. Lecellier, et al. (2004). "Probing the microRNA and small interfering RNA pathways with virus-encoded suppressors of RNA silencing." Plant Cell 16(5):1235-1250.
Edgar, R. C. (2004). "MUSCLE:a multiple sequence alignment method with reduced time and space complexity." BMC Bio informatics 5:113.
Eleftheriou, M., R. Germain, et al. (2006). "Thermal denaturing of mutant lysozyme with both OPLSAA and CHARMM force fields." J. Am. Chem. Soc.128:13388-13395.
Faith, J. J., B. Hayete, et al. (2007). "Large-scale mapping and validation of Escherichia coli transcriptional regulation from a compendium of expression profiles." Plos Biol 5(1):e8.
Fersht, A. R. and V. Daggett (2002). "Protein folding and unfolding at atomic resolution." Cell 108(4):573-582.
Fire, A., S. Q. Xu, et al. (1998). "Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans." Nature 391(6669):806-811.
Fitch, W. M., R. M. Bush, et al. (1997). "Long term trends in the evolution of H(3) HA1 human influenza type A." Proc Natl Acad Sci U S A 94(15):7712-7718.
Fouchier, R. A., V. Munster, et al. (2005). "Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls." J Virol 79(5):2814-2822.
Gamblin, S. J., L. F. Haire, et al. (2004). "The structure and receptor binding properties of the 1918 influenza hemagglutinin." Science 303(5665):1838-1842.
Garcia, A. E. and J. N. Onuchic (2003). "Folding a protein in a computer:An atomic description of the folding/unfolding of protein A." Proc Natl Acad Sci U S A 100(24):13898-13903.
Glaser, F., T. Pupko, et al. (2003). "ConSurf:identification of functional regions in proteins by surface-mapping of phylogenetic information." Bioinformatics 19(1):163-164.
Gunawardane, L. S., K. Saito, et al. (2007). "A slicer-mediated mechanism for repeat-associated siRNA 5' end formation in Drosophila." Science 315(5818):1587-1590.
Ha, Y., D. J. Stevens, et al. (2003). "X-ray structure of the hemagglutinin of a potential H3 avian progenitor of the 1968 Hong Kong pandemic influenza virus." Virology 309(2):209-218.
Hamilton, A. J. and D. C. Baulcombe (1999). "A species of small antisense RNA in posttranscriptional gene silencing in plants." Science 286(5441):950-952.
Hayward, S. and R. A. Lee (2002). "Improvements in the analysis of domain motions in proteins from conformational change:DynDom version 1.50." J. Mol. Graph. Model.21(3):181-183.
Hilleman, M. R. (2002). "Realities and enigmas of human viral influenza:pathogenesis, epidemiology and control." Vaccine 20(25-26):3068-3087.
Hillman, B. I. (1987). "A defective interfering RNA that contains a mosaic of a plant virus genome." Cell 51:427-433.
Holmes, E. C., E. Ghedin, et al. (2005). "Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses." Plos Biol 3(9):e300.
Horimoto, T. and Y. Kawaoka (2005). "Influenza:lessons from past pandemics, warnings from current incidents." Nat Rev Microbiol 3(8):591-600.
Huelsenbeck, J. P. and K. A. Dyer (2004). "Bayesian estimation of positively selected sites." J Mol Evol 58(6):661-672.
Hutter, D. M. a. J. u. (2000). Ab initio molecular dynamics:Theory and Implementation. Modern Methods and Algorithms of Quantum Chemistry,. J" ulich. John von Neumann Institute for Computing.1:149.
Jayachandran, G., M. R. Shirts, et al. (2006). "Parallelized-over-parts computation of absolute binding free energy with docking and molecular dynamics." J Chem Phys 125(8): 084901.
Jones-Rhoades, M. W., D. P. Bartel, et al. (2006). "MicroRNAs and their regulatory roles in plants." Annu Rev Plant Biol 57:19-53.
Jorgensen, W. L., J. Chandrasekhar, et al. (1983). "Comparison of simple potential functions for simulating liquid water." J Chem Phys 79(2):926-935.
Karplus, M. (2003). "Molecular dynamics of biological macromolecules:A brief history and perspective." Biopolymers 68(3):350-358.
Kasschau, K. D. and J. C. Carrington (1998). "A counterdefensive strategy of plant viruses: suppression of posttranscriptional gene silencing." Cell 95:461-470.
Kawasaki, H. and K. Taira (2004). "Induction of DNA methylation and gene silencing by short interfering RNAs in human cells." Nature 431(7005):211-217.
Kim, V. N., J. Han, et al. (2009). "Biogenesis of small RNAs in animals." Nat Rev Mol Cell Biol 10(2):126-139.
Koelle, K., S. Cobey, et al. (2006). "Epochal evolution shapes the phylodynamics of interpandemic influenza A (H3N2) in humans." Science 314(5807):1898-1903.
Kokubo, H. and Y. Okamoto (2004). "Prediction of transmembrane helix configurations by replica-exchange simulations." CPL 383(3-4):397-402.
Kumar, S., C. Huang, et al. (2007). "Scalable Molecular Dynamics with NAMD on Blue Gene/L " Ibm J Res Dev 52(No.1/2).
Kumar, S., C. Huang, et al. (2008). "Scalable Molecular Dynamics with NAMD on Blue Gene/L " IBM Journal of Research and Development 52(No.1/2):177-188.
Lakatos, L., T. Csorba, et al. (2006). "Small RNA binding is a common strategy to suppress RNA silencing by several viral suppressors." EMBO J.25(12):2768-2780.
Lakatos, L., G. Szittya, et al. (2004). "Molecular mechanism of RNA silencing suppression mediated by p19 protein of tombusviruses." EMBO J.23(4):876-884.
Landau, M., I. Mayrose, et al. (2005). "ConSurf 2005:the projection of evolutionary conservation scores of residues on protein structures." Nucleic Acids Res 33(Web Server issue):W299-302.
Leach, A. R. (2001). Molecular Modeling Principals and Applications, Pearson Education Limited.
Lecellier, C. H., P. Dunoyer, et al. (2005). "A cellular MicroRNA mediates antiviral defense in human cells." Science 308(5721):557-560.
Lee, R. C., R. L. Feinbaum, et al. (1993). "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14." Cell 75(5):843-854.
Levine, I. N. (1991). Quantum Chemistry. Englewood Cliffs, New Jersey, Prentice-Hall.
Li, C. and W. H. Wong (2003). DNA-Chip Analyzer (dChip). New York, Springer.
Li, W. X. and S. W. Ding (2001). "Viral suppressors of RNA silencing." Curr Opin Biotech 12(2):150-154.
Li, W. X., H. W. Li, et al. (2004). "Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing." P Natl Acad Sci USA 101(5):1350-1355.
Li, X., J. Li, et al. (2006). "Hydration and Dewetting near Fluorinated Superhydrophobic Plates." J. Am. Chem. Soc.128:12439-12447.
Lifson, M. B. a. S. (1967). "Potential Functions and Conformations in Cycloalkanes." Tetrahedron 23.
Lingel, A., B. Simon, et al. (2003). "Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain." Nature 426(6965):465-469.
Lingel, A., B. Simon, et al. (2004). "Nucleic acid 3'-end recognition by the Argonaute2 PAZ domain." Nat Struct Mol Biol 11(6):576-577.
Lippman, Z. and R. Martienssen (2004). "The role of RNA interference in heterochromatic silencing." Nature 431(7006): 364-370.
Liu, P., X. H. Huang, et al. (2005). "Observation of a dewetting transition in the collapse of the melittin tetramer." Nature 437(7055):159-162.
Ma, J. B., K. Ye, et al. (2004). "Structural basis for overhang-specific small interfering RNA recognition by the PAZ domain." Nature 429(6989):318-322.
MacKerell, A. D., Jr., N. Banavali, et al. (2000). "Development and current status of the CHARMM force field for nucleic acids." Biopolymers 56(4):257-265.
Mackerell, A. D., Jr., M. Feig, et al. (2004). "Extending the treatment of backbone energetics in protein force fields:limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations." J Comput Chem 25(11):1400-1415.
Mallory, A. C. and H. Vaucheret (2006). "Functions of microRNAs and related small RNAs in plants." Nat Genet 38 Suppl:S31-36.
Margolin, A. A., I. Nemenman, et al. (2006). "ARACNE:an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context." BMC Bioinformatics 7 Suppl 1:S7.
Mark, A. E. and W. F. van Gunsteren (1994). "Decomposition of the free energy of a system in terms of specific interactions. Implications for theoretical and experimental studies." J Mol Biol 240(2):167-176.
Martinez, J., A. Patkaniowska, et al. (2002). "Single-stranded antisense siRNAs guide target RNA cleavage in RNAi." Cell 110(5):563-574.
Matranga, C., Y. Tomari, et al. (2005). "Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes." Cell 123(4):607-620.
Ming, D., M. E. Wall, et al. (2007). "Domain motions of Argonaute, the catalytic engine of RNA interference." BMC Bioinformatics 8:470.
Morris, K. V., S. W. Chan, et al. (2004). "Small interfering RNA-induced transcriptional gene silencing in human cells." Science 305(5688):1289-1292.
Nelson, M. I., L. Simonsen, et al. (2006). "Stochastic processes are key determinants of short-term evolution in influenza a virus." PLoS Pathog 2(12):e125.
Neria, E. and M. Karplus (1996). "A position dependent friction model for solution reactions in the high friction regime:Proton transfer in triosephosphate isomerase (TIM)." J Chem Phys 105(24):10812-10818.
Nielsen, R. and Z. Yang (1998). "Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene." Genetics 148(3):929-936.
Novina, C. D. and P. A. Sharp (2004). "The RNAi revolution." Nature 430(6996):161-164.
Omarov, R. T., J. J. Ciomperlik, et al. (2007). "RNAi-associated ssRNA-specific ribonucleases in Tombusvirus P19 mutant-infected plants and evidence for a discrete siRNA-containing effector complex." Proc Natl Acad Sci U S A 104(5):1714-1719.
P. Hohenberg, W. K. (1964). "Inhomogeneous Electron Gas." PhRv 136(3B):8.
Pan, Y., D. Gao, et al. (2007). "Free energy perturbation (FEP) simulation on the transition states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants." J Am Chem Soc 129(44):13537-13543.
Papp I, Mette MF, et al. (2003). "Evidence for nuclear processing of plant micro RNA and short-interfering RNA precursors." Plant Physiol.132:1382-1390.
Parker, J. S., S. M. Roe, et al. (2004). "Crystal structure of a PIWI protein suggests mechanisms for siRNA recognition and slicer activity." EMBO J.23(24):4727-4737.
Parker, J. S., S. M. Roe, et al. (2005). "Structural insights into mRNA recognition from a PIWI domain-siRNA guide complex." Nature 434(7033):663-666.
Patel, S., A. D. Mackerell, Jr., et al. (2004). "CHARMM fluctuating charge force field for proteins:II protein/solvent properties from molecular dynamics simulations using a nonadditive electrostatic model." J Comput Chem 25(12):1504-1514.
Pham, J. W., J. L. Pellino, et al. (2004). "A Dicer-2-dependent 80S complex cleaves targeted mRNAs during RNAi in Drosophila." Cell 117(1):83-94.
Phillips, J. C., R. Braun, et al. (2005). "Scalable molecular dynamics with NAMD." J Comput Chem 26(16):1781-1802.
Plotkin, J. B. and J. Dushoff (2003). "Codon bias and frequency-dependent selection on the hemagglutinin epitopes of influenza A virus." Proc Natl Acad Sci U S A 100(12):7152-7157.
Poornam, G. P., A. Matsumoto, et al. (2009). "A method for the analysis of domain movements in large biomolecular complexes." Proteins 76(1):201-212.
Qiu, W. P., J. W. Park, et al. (2002). "Tombusvirus p19-mediated suppression of virus-induced gene silencing is controlled by genetic and dosage features that influence pathogenicity." Mol. Plant Microbe Interact.15(3):269-280.
Qu, F. and T. J. Morris (2002). "Efficient infection of Nicotiana benthamiana by Tomato bushy stunt virus is facilitated by the coat protein and maintained by p19 through suppression of gene silencing." Mol. Plant Microbe Interact.15(3):193-202.
Qu, F. and T. J. Morris (2005). "Suppressors of RNA silencing encoded by plant viruses and their role in virus infection." FEBS Lett.579:5958-5964.
Rambaut, A., O. G. Pybus, et al. (2008). "The genomic and epidemiological dynamics of human influenza A virus." Nature 453(7195):615-U612.
Rivas, F. V., N. H. Tolia, et al. (2005). "Purified Argonaute2 and an siRNA form recombinant human RISC." Nat Struct Mol Biol 12(4):340-349.
Roth, B. M., G. J. Pruss, et al. (2004). "Plant viral suppressors of RNA silencing." Virus Res. 102:97-108.
Schlick, T. (2002). Molecular Modeling and Simulation:An Interdisciplinary Guide. New York, NY, Springer.
Scholthof, H. B. (2006). "Timeline-The Tombusvirus-encoded P19:from irrelevance to elegance." Nat Rev Microbiol 4(5):405-411.
Schwarz, D. S., G. Hutvagner, et al. (2003). "Asymmetry in the assembly of the RNAi enzyme complex." Cell 115(2):199-208.
Shih, A. C, T. C. Hsiao, et al. (2007). "Simultaneous amino acid substitutions at antigenic sites drive influenza A hemagglutinin evolution." Proc Natl Acad Sci U S A 104(15):6283-6288.
Shors, T. (2008). Understanding Viruses, Jones and Bartlett Publishers.
Silhavy, D., A. Molnar, et al. (2002). "A viral protein suppresses RNA silencing and binds silencing-generated,21-to 25-nucleotide double-stranded RNAs." EMBO J.21(12): 3070-3080.
Smith, D. J., A. S. Lapedes, et al. (2004). "Mapping the antigenic and genetic evolution of influenza virus." Science 305(5682):371-376.
Snow, C. D., N. Nguyen, et al. (2002). "Absolute comparison of simulated and experimental protein-folding dynamics." Nature 420(6911):102-106.
Song, J. J., J. Liu, et al. (2003). "The crystal structure of the Argonaute2 PAZ domain reveals an RNA binding motif in RNAi effector complexes." Nat Struct Biol 10(12):1026-1032.
Song, J. J., S. K. Smith, et al. (2004). "Crystal structure of Argonaute and its implications for RISC slicer activity." Science 305(5689):1434-1437.
Stevens, J., O. Blixt, et al. (2006). "Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus." Science 312(5772):404-410.
Straub, J. E. and D. Thirumalai (1993). "Theoretical probes of conformational fluctuations in S-peptide and RNase A/3'-UMP enzyme product complex." Proteins 15:360-373.
Suzuki, Y. (2004). "New methods for detecting positive selection at single amino acid sites." J Mol Evol 59(1):11-19.
Suzuki, Y. and T. Gojobori (1999). "A method for detecting positive selection at single amino acid sites." Mol Biol Evol 16(10):1315-1328.
Szittya, G., Molnar A, et al. (2002). "Short defective interfering RNAs of tombusviruses are not targeted but trigger post-transcriptional gene silencing against their helper virus." Plant Cell 14:1-15.
Tamura, K., J. Dudley, et al. (2007). "MEGA4:Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0." Mol Biol Evol 24(8):1596-1599.
Thorpe, I. F. and C. L. Brooks Iii (2007). "Molecular evolution of affinity and flexibility in the immune system." Proc Natl Acad Sci U S A 104(21):8821.
Thrope, I. F. and C. L. Brooks (2007). "Molecular evolution of affinity and flexibility in the immune system." Proc. Natl. Acad. Sci.104:8821-8826.
Tirado-Rives, J. and W. L. Jorgensen (2006). "Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding." J Med Chem 49: 5880-5884
Tomari, Y. and P. D. Zamore (2005). "Perspective:machines for RNAi." Gene Dev 19(5):517-529.
Tucker, M. J., R. Oyola, et al. (2006). "A Novel Fluorescent Probe for Protein Binding and Folding Studies:P-Cyano-Phenylalanine." Biopolymers 83:571-576.
van Nimwegen, E. (2006). "Epidemiology. Influenza escapes immunity along neutral networks." Science 314(5807):1884-1886.
Vargason, J. M., G. Szittya, et al. (2003). "Size selective recognition of siRNA by an RNA silencing suppressor." Cell 115(7):799-811.
Verdel, A. and D. Moazed (2005). "RNAi-directed assembly of heterochromatin in fission yeast." Febs Lett 579(26):5872-5878.
Vionnet, O., Y. M. Pinto, et al. (1999). "Suppression of gene silencing:a general strategy used by diverse DNA and RNA viruses of plants." Proc. Natl Acad. Sci. USA 96:14147-14152.
Voinnet, O. (2001). "RNA silencing as a plant immune system against viruses." Trends Genet 17(8):449-459.
Voinnet, O. (2005). "Induction and suppression of RNA silencing:insights from viral infections." Nature Rev. Genetics 6:206-220.
Wang, Y, S. Juranek, et al. (2008). "Structure of an argonaute silencing complex with a seed-containing guide DNA and target RNA duplex." Nature 456(7224):921-926.
Wang, Y., S. Juranek, et al. (2009). "Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes." Nature 461(7265):754-761.
Wang, Y., G. Sheng, et al. (2008). "Structure of the guide-strand-containing argonaute silencing complex." Nature 456(7219):209-213.
Warshel, A. (1984). "Simulating the Energetics and Dynamics of Enzymatic Reactions " in Specificity in Biological Interactions, Pontificiae Academiae Scientiarum Scripta Varia 55:60-81.
Warshel, A., P. K. Sharma, et al. (2006). "Modeling Electrostatic Effects in Proteins,,1764 (11), 1647-1676." Biochim. Biophys. Acta 1764(11):1647-1676.
Warshel, S. L. a. A. (1968). "A Consistent Force Field for Calculation of Conformations Vibrational Spectra and Enthalpies of Cycloalkane and n-Alkane Molecules." J. Chem. Phys.49.
Webster, R. G., W. J. Bean, et al. (1992). "Evolution and ecology of influenza A viruses." Microbiol Rev 56(1):152-179.
Webster, R. G., W. G. Laver, et al. (1982). "Molecular mechanisms of variation in influenza viruses." Nature 296(5853):115-121.
Weis, W., J. H. Brown, et al. (1988). "Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid." Nature 333(6172):426-431.
Weis, W. I., A. T. Brunger, et al. (1990). "Refinement of the influenza virus hemagglutinin by simulated annealing." J Mol Biol 212(4):737-761.
Wightman, B., I. Ha, et al. (1993). "Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans." Cell 75(5):855-862.
Xia, Z., Z. Zhu, et al. (2009). "Recognition mechanism of siRNA by viral p19 suppressor of RNA silencing:a molecular dynamics study." Biophys J 96(5):1761-1769.
Yan, K. S., S. Yan, et al. (2003). "Structure and conserved RNA binding of the PAZ domain.' Nature 426(6965):468-474.
Yang, W., R. Bitetti-Putzer, et al. (2004). "Free energy simulations:use of reverse cumulative averaging to determine the equilibrated region and the time required for convergence." J Chem Phys 120(6):2618-2628.
Yang, Z., R. Nielsen, et al. (2000). "Codon-substitution models for heterogeneous selection pressure at amino acid sites." Genetics 155(1):431-449.
Yang, Z. and W. J. Swanson (2002). "Codon-substitution models to detect adaptive evolution that account for heterogeneous selective pressures among site classes." Mol Biol Evol 19(1):49-57.
Ye, K. Q., L. Malinina, et al. (2003). "Recognition of small interfering RNA by a viral suppressor of RNA silencing." Nature 426(6968):874-878.
Yuan, Y. R., Y. Pei, et al. (2005). "Crystal structure of A. aeolicus argonaute, a site-specific DNA-guided endoribonuclease, provides insights into RISC-mediated mRNA cleavage." Mol Cell 19(3):405-419.
Zhang, B., X. Pan, et al. (2006). "Plant microRNA:a small regulatory molecule with big impact." Dev Biol 289(1):3-16.
Zhou, R., P. Das, et al. (2008). "Single Mutation Induced H3N2 Hemagglutinin Antibody Neutralization:A Free Energy Perturbation Study." J. Phys. Chem. B 112:15813-15820.
Zhou, R. H., X. H. Huang, et al. (2004). "Hydrophobic collapse in multidomain protein folding." Science 305(5690):1605-1609.
Ahlquist, P. (2002). "RNA-dependent RNA polymerases, viruses, and RNA silencing." Science 296(5571):1270-1273.
Alder, B. J. a. W., T. E. (1957). "Phase transition for a hard sphere system." J Chem Phvs 27:2.
Anandalakshmi R, G. J. Pruss, et al. (1998). "A viral suppressor of gene silencing in plants." Proc. Natl Acad. Sci. USA 95:13079-13084.
Aqvist, J. and A. Warshel (1989). "Energetics of ion permeation through membrane channels. Solvation of Na+by gramicidin A." Biophys J 56(1):171-182.
Bao Y., P. B., D. Dernovoy, B. Kiryutin, L. Zaslavsky, T. Tatusova, J. Ostell, and D. Lipman. (2008). "The influenza virus resource at the National Center for Biotechnology Information." J. Virol.82(2):596-601.
Baulcombe, D. (2002). "Viral suppression of systemic silencing." Trends Microbiol 10(7):306-308.
Baulcombe, D. (2004). "RNA silencing in plants." Nature 431:356-363.
Bernstein, E., A. A. Caudy, et al. (2001). "Role for a bidentate ribonuclease in the initiation step of RNA interference." Nature 409(6818):363-366.
Bird, A. (2002). "DNA methylation patterns and epigenetic memory." Genes Dev 16(1):6-21.
Boresch, S. and M. Karplus (1995). "The meaning of component analysis:decomposition of the free energy in terms of specific interactions." J Mol Biol 254(5):801-807.
Brady, G. P. and K. A. Sharp (1995). "Decomposition of interaction free energies in proteins and other complex systems." J Mol Biol 254(1):77-85.
Bren, M., J. Florian, et al. (2007). "Do all pieces make a whole? Thiele cumulants and the free energy decomposition." Theoretical Chemistry Accounts 117(4):535-540.
Brooks, B. R., C. L. Brooks,3rd, et al. (2009). "CHARMM:the biomolecular simulation program." J Comput Chem 30(10):1545-1614.
Brooks, B. R., R. E. Bruccoeri, et al. (1983). "CHARMM:A program for macromolecular energy, minimization, and dynamics calculations." J Comput Chem 4(2):187-217.
Brooks, C. L., M. Gruebele, et al. (1998). "Chemical physics of protein folding." Proc Natl Acad Sci U S A 95(19):11037-11038.
Brooks, C. L., J. N. Onuchic, et al. (2001). "Statistical thermodynamics-Taking a walk on a landscape." Science 293(5530):612-613.
Bush, R. M., C. A. Bender, et al. (1999). "Predicting the evolution of human influenza A.' Science 286(5446):1921-1925.
Bush, R. M., W. M. Fitch, et al. (1999). "Positive selection on the H3 hemagglutinin gene of human influenza virus A." Mol Biol Evol 16(11):1457-1465.
Butte, A. J. and I. S. Kohane (2000). "Mutual information relevance networks:functional genomic clustering using pairwise entropy measurements." Pacific Symposium on Biocomputing:418-429.
Butte, A. J., P. Tamayo, et al. (2000). "Discovering functional relationships between RNA expression and chemotherapeutic susceptibility using relevance networks." Proc Natl Acad Sci U S A 97(22):12182-12186.
Calabrese, J. M. and P. A. Sharp (2006). "Characterization of the short RNAs bound by the P19 suppressor of RNA silencing in mouse embryonic stem cells." Rna 12(12):2092-2102.
Chapman, E. J., A. I. Prokhnevsky, et al. (2004). "Viral RNA silencing suppressors inhibit the micro RNA pathway at an intermediate step." Gene Dev 18(10):1179-1186.
Chen, R. and E. C. Holmes (2006). "Avian influenza virus exhibits rapid evolutionary dynamics." Mol Biol Evol 23(12):2336-2341.
Chu, M, B. Desvoyes, et al. (2000). "Genetic dissection of tomato bushy stunt virus p19-protein-mediated host-dependent symptom induction and systemic invasion." Virology 266(1):79-87.
Cox, N. J. and K. Subbarao (2000). "Global epidemiology of influenza:past and present." Annu Rev Med 51:407-421.
Cramer, C. (2002). Essentials of Computational Chemistry., Chichester.
D. van der Spoel, E. Lindahl, et al. (2005). "Gromacs User Manual version 4.0." www.gromacs.org.
Das, P., J. Li, et al. (2009). "Free energy simulations reveal a double mutant avian H5N1 virus hemagglutinin with altered receptor binding specificity." J Comput Chem.
DeLano, W. L. (2008). "The PyMOL Molecular Graphics System." DeLano Scientific:San Carlos, CA, USA.
Deng, Y. and B. Roux (2006). "Calculation of standard binding free energies:aromatic molecules in the T4 lysozyme L99A mutant." J. Chem. Theo. Comp.2:1255-1273.
Deng, Y. Q. and B. Roux (2006). "Calculation of standard binding free energies:Aromatic molecules in the T4 lysozyme L99A mutant." Journal of Chemical Theory and Computation 2(5):1255-1273.
Desemo, M. and C. Holm (1998). "How to mesh up Ewald sums. Ⅰ. A theoretical and numerical comparison of various particle mesh routines." J Chem Phys 109(18):7678-7693.
Deserno, M. and C. Holm (1998). "How to mesh up Ewald sums. Ⅱ. An accurate error estimate for the particle-particle-particle-mesh algorithm." J Chem Phys 109(18):7694-7701.
Du, X., Z. Wang, et al. (2008). "Networks of genomic co-occurrence capture characteristics of human influenza A (H3N2) evolution." Genome Res 18(1):178-187.
Dunoyer, P., C. H. Lecellier, et al. (2004). "Probing the microRNA and small interfering RNA pathways with virus-encoded suppressors of RNA silencing." Plant Cell 16(5):1235-1250.
Edgar, R. C. (2004). "MUSCLE:a multiple sequence alignment method with reduced time and space complexity." BMC Bio informatics 5:113.
Eleftheriou, M., R. Germain, et al. (2006). "Thermal denaturing of mutant lysozyme with both OPLSAA and CHARMM force fields." J. Am. Chem. Soc.128:13388-13395.
Faith, J. J., B. Hayete, et al. (2007). "Large-scale mapping and validation of Escherichia coli transcriptional regulation from a compendium of expression profiles." Plos Biol 5(1):e8.
Fersht, A. R. and V. Daggett (2002). "Protein folding and unfolding at atomic resolution." Cell 108(4):573-582.
Fire, A., S. Q. Xu, et al. (1998). "Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans." Nature 391(6669):806-811.
Fitch, W. M., R. M. Bush, et al. (1997). "Long term trends in the evolution of H(3) HA1 human influenza type A." Proc Natl Acad Sci U S A 94(15):7712-7718.
Fouchier, R. A., V. Munster, et al. (2005). "Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls." J Virol 79(5):2814-2822.
Gamblin, S. J., L. F. Haire, et al. (2004). "The structure and receptor binding properties of the 1918 influenza hemagglutinin." Science 303(5665):1838-1842.
Garcia, A. E. and J. N. Onuchic (2003). "Folding a protein in a computer:An atomic description of the folding/unfolding of protein A." Proc Natl Acad Sci U S A 100(24):13898-13903.
Glaser, F., T. Pupko, et al. (2003). "ConSurf:identification of functional regions in proteins by surface-mapping of phylogenetic information." Bioinformatics 19(1):163-164.
Gunawardane, L. S., K. Saito, et al. (2007). "A slicer-mediated mechanism for repeat-associated siRNA 5' end formation in Drosophila." Science 315(5818):1587-1590.
Ha, Y., D. J. Stevens, et al. (2003). "X-ray structure of the hemagglutinin of a potential H3 avian progenitor of the 1968 Hong Kong pandemic influenza virus." Virology 309(2):209-218.
Hamilton, A. J. and D. C. Baulcombe (1999). "A species of small antisense RNA in posttranscriptional gene silencing in plants." Science 286(5441):950-952.
Hayward, S. and R. A. Lee (2002). "Improvements in the analysis of domain motions in proteins from conformational change:DynDom version 1.50." J. Mol. Graph. Model.21(3):181-183.
Hilleman, M. R. (2002). "Realities and enigmas of human viral influenza:pathogenesis, epidemiology and control." Vaccine 20(25-26):3068-3087.
Hillman, B. I. (1987). "A defective interfering RNA that contains a mosaic of a plant virus genome." Cell 51:427-433.
Holmes, E. C., E. Ghedin, et al. (2005). "Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses." Plos Biol 3(9):e300.
Horimoto, T. and Y. Kawaoka (2005). "Influenza:lessons from past pandemics, warnings from current incidents." Nat Rev Microbiol 3(8):591-600.
Huelsenbeck, J. P. and K. A. Dyer (2004). "Bayesian estimation of positively selected sites." J Mol Evol 58(6):661-672.
Hutter, D. M. a. J. u. (2000). Ab initio molecular dynamics:Theory and Implementation. Modern Methods and Algorithms of Quantum Chemistry,. J" ulich. John von Neumann Institute for Computing.1:149.
Jayachandran, G., M. R. Shirts, et al. (2006). "Parallelized-over-parts computation of absolute binding free energy with docking and molecular dynamics." J Chem Phys 125(8): 084901.
Jones-Rhoades, M. W., D. P. Bartel, et al. (2006). "MicroRNAs and their regulatory roles in plants." Annu Rev Plant Biol 57:19-53.
Jorgensen, W. L., J. Chandrasekhar, et al. (1983). "Comparison of simple potential functions for simulating liquid water." J Chem Phys 79(2):926-935.
Karplus, M. (2003). "Molecular dynamics of biological macromolecules:A brief history and perspective." Biopolymers 68(3):350-358.
Kasschau, K. D. and J. C. Carrington (1998). "A counterdefensive strategy of plant viruses: suppression of posttranscriptional gene silencing." Cell 95:461-470.
Kawasaki, H. and K. Taira (2004). "Induction of DNA methylation and gene silencing by short interfering RNAs in human cells." Nature 431(7005):211-217.
Kim, V. N., J. Han, et al. (2009). "Biogenesis of small RNAs in animals." Nat Rev Mol Cell Biol 10(2):126-139.
Koelle, K., S. Cobey, et al. (2006). "Epochal evolution shapes the phylodynamics of interpandemic influenza A (H3N2) in humans." Science 314(5807):1898-1903.
Kokubo, H. and Y. Okamoto (2004). "Prediction of transmembrane helix configurations by replica-exchange simulations." CPL 383(3-4):397-402.
Kumar, S., C. Huang, et al. (2007). "Scalable Molecular Dynamics with NAMD on Blue Gene/L " Ibm J Res Dev 52(No.1/2).
Kumar, S., C. Huang, et al. (2008). "Scalable Molecular Dynamics with NAMD on Blue Gene/L " IBM Journal of Research and Development 52(No.1/2):177-188.
Lakatos, L., T. Csorba, et al. (2006). "Small RNA binding is a common strategy to suppress RNA silencing by several viral suppressors." EMBO J.25(12):2768-2780.
Lakatos, L., G. Szittya, et al. (2004). "Molecular mechanism of RNA silencing suppression mediated by p19 protein of tombusviruses." EMBO J.23(4):876-884.
Landau, M., I. Mayrose, et al. (2005). "ConSurf 2005:the projection of evolutionary conservation scores of residues on protein structures." Nucleic Acids Res 33(Web Server issue):W299-302.
Leach, A. R. (2001). Molecular Modeling Principals and Applications, Pearson Education Limited.
Lecellier, C. H., P. Dunoyer, et al. (2005). "A cellular MicroRNA mediates antiviral defense in human cells." Science 308(5721):557-560.
Lee, R. C., R. L. Feinbaum, et al. (1993). "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14." Cell 75(5):843-854.
Levine, I. N. (1991). Quantum Chemistry. Englewood Cliffs, New Jersey, Prentice-Hall.
Li, C. and W. H. Wong (2003). DNA-Chip Analyzer (dChip). New York, Springer.
Li, W. X. and S. W. Ding (2001). "Viral suppressors of RNA silencing." Curr Opin Biotech 12(2):150-154.
Li, W. X., H. W. Li, et al. (2004). "Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing." P Natl Acad Sci USA 101(5):1350-1355.
Li, X., J. Li, et al. (2006). "Hydration and Dewetting near Fluorinated Superhydrophobic Plates." J. Am. Chem. Soc.128:12439-12447.
Lifson, M. B. a. S. (1967). "Potential Functions and Conformations in Cycloalkanes." Tetrahedron 23.
Lingel, A., B. Simon, et al. (2003). "Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain." Nature 426(6965):465-469.
Lingel, A., B. Simon, et al. (2004). "Nucleic acid 3'-end recognition by the Argonaute2 PAZ domain." Nat Struct Mol Biol 11(6):576-577.
Lippman, Z. and R. Martienssen (2004). "The role of RNA interference in heterochromatic silencing." Nature 431(7006): 364-370.
Liu, P., X. H. Huang, et al. (2005). "Observation of a dewetting transition in the collapse of the melittin tetramer." Nature 437(7055):159-162.
Ma, J. B., K. Ye, et al. (2004). "Structural basis for overhang-specific small interfering RNA recognition by the PAZ domain." Nature 429(6989):318-322.
MacKerell, A. D., Jr., N. Banavali, et al. (2000). "Development and current status of the CHARMM force field for nucleic acids." Biopolymers 56(4):257-265.
Mackerell, A. D., Jr., M. Feig, et al. (2004). "Extending the treatment of backbone energetics in protein force fields:limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations." J Comput Chem 25(11):1400-1415.
Mallory, A. C. and H. Vaucheret (2006). "Functions of microRNAs and related small RNAs in plants." Nat Genet 38 Suppl:S31-36.
Margolin, A. A., I. Nemenman, et al. (2006). "ARACNE:an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context." BMC Bioinformatics 7 Suppl 1:S7.
Mark, A. E. and W. F. van Gunsteren (1994). "Decomposition of the free energy of a system in terms of specific interactions. Implications for theoretical and experimental studies." J Mol Biol 240(2):167-176.
Martinez, J., A. Patkaniowska, et al. (2002). "Single-stranded antisense siRNAs guide target RNA cleavage in RNAi." Cell 110(5):563-574.
Matranga, C., Y. Tomari, et al. (2005). "Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes." Cell 123(4):607-620.
Ming, D., M. E. Wall, et al. (2007). "Domain motions of Argonaute, the catalytic engine of RNA interference." BMC Bioinformatics 8:470.
Morris, K. V., S. W. Chan, et al. (2004). "Small interfering RNA-induced transcriptional gene silencing in human cells." Science 305(5688):1289-1292.
Nelson, M. I., L. Simonsen, et al. (2006). "Stochastic processes are key determinants of short-term evolution in influenza a virus." PLoS Pathog 2(12):e125.
Neria, E. and M. Karplus (1996). "A position dependent friction model for solution reactions in the high friction regime:Proton transfer in triosephosphate isomerase (TIM)." J Chem Phys 105(24):10812-10818.
Nielsen, R. and Z. Yang (1998). "Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene." Genetics 148(3):929-936.
Novina, C. D. and P. A. Sharp (2004). "The RNAi revolution." Nature 430(6996):161-164.
Omarov, R. T., J. J. Ciomperlik, et al. (2007). "RNAi-associated ssRNA-specific ribonucleases in Tombusvirus P19 mutant-infected plants and evidence for a discrete siRNA-containing effector complex." Proc Natl Acad Sci U S A 104(5):1714-1719.
P. Hohenberg, W. K. (1964). "Inhomogeneous Electron Gas." PhRv 136(3B):8.
Pan, Y., D. Gao, et al. (2007). "Free energy perturbation (FEP) simulation on the transition states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants." J Am Chem Soc 129(44):13537-13543.
Papp I, Mette MF, et al. (2003). "Evidence for nuclear processing of plant micro RNA and short-interfering RNA precursors." Plant Physiol.132:1382-1390.
Parker, J. S., S. M. Roe, et al. (2004). "Crystal structure of a PIWI protein suggests mechanisms for siRNA recognition and slicer activity." EMBO J.23(24):4727-4737.
Parker, J. S., S. M. Roe, et al. (2005). "Structural insights into mRNA recognition from a PIWI domain-siRNA guide complex." Nature 434(7033):663-666.
Patel, S., A. D. Mackerell, Jr., et al. (2004). "CHARMM fluctuating charge force field for proteins:II protein/solvent properties from molecular dynamics simulations using a nonadditive electrostatic model." J Comput Chem 25(12):1504-1514.
Pham, J. W., J. L. Pellino, et al. (2004). "A Dicer-2-dependent 80S complex cleaves targeted mRNAs during RNAi in Drosophila." Cell 117(1):83-94.
Phillips, J. C., R. Braun, et al. (2005). "Scalable molecular dynamics with NAMD." J Comput Chem 26(16):1781-1802.
Plotkin, J. B. and J. Dushoff (2003). "Codon bias and frequency-dependent selection on the hemagglutinin epitopes of influenza A virus." Proc Natl Acad Sci U S A 100(12):7152-7157.
Poornam, G. P., A. Matsumoto, et al. (2009). "A method for the analysis of domain movements in large biomolecular complexes." Proteins 76(1):201-212.
Qiu, W. P., J. W. Park, et al. (2002). "Tombusvirus p19-mediated suppression of virus-induced gene silencing is controlled by genetic and dosage features that influence pathogenicity." Mol. Plant Microbe Interact.15(3):269-280.
Qu, F. and T. J. Morris (2002). "Efficient infection of Nicotiana benthamiana by Tomato bushy stunt virus is facilitated by the coat protein and maintained by p19 through suppression of gene silencing." Mol. Plant Microbe Interact.15(3):193-202.
Qu, F. and T. J. Morris (2005). "Suppressors of RNA silencing encoded by plant viruses and their role in virus infection." FEBS Lett.579:5958-5964.
Rambaut, A., O. G. Pybus, et al. (2008). "The genomic and epidemiological dynamics of human influenza A virus." Nature 453(7195):615-U612.
Rivas, F. V., N. H. Tolia, et al. (2005). "Purified Argonaute2 and an siRNA form recombinant human RISC." Nat Struct Mol Biol 12(4):340-349.
Roth, B. M., G. J. Pruss, et al. (2004). "Plant viral suppressors of RNA silencing." Virus Res. 102:97-108.
Schlick, T. (2002). Molecular Modeling and Simulation:An Interdisciplinary Guide. New York, NY, Springer.
Scholthof, H. B. (2006). "Timeline-The Tombusvirus-encoded P19:from irrelevance to elegance." Nat Rev Microbiol 4(5):405-411.
Schwarz, D. S., G. Hutvagner, et al. (2003). "Asymmetry in the assembly of the RNAi enzyme complex." Cell 115(2):199-208.
Shih, A. C, T. C. Hsiao, et al. (2007). "Simultaneous amino acid substitutions at antigenic sites drive influenza A hemagglutinin evolution." Proc Natl Acad Sci U S A 104(15):6283-6288.
Shors, T. (2008). Understanding Viruses, Jones and Bartlett Publishers.
Silhavy, D., A. Molnar, et al. (2002). "A viral protein suppresses RNA silencing and binds silencing-generated,21-to 25-nucleotide double-stranded RNAs." EMBO J.21(12): 3070-3080.
Smith, D. J., A. S. Lapedes, et al. (2004). "Mapping the antigenic and genetic evolution of influenza virus." Science 305(5682):371-376.
Snow, C. D., N. Nguyen, et al. (2002). "Absolute comparison of simulated and experimental protein-folding dynamics." Nature 420(6911):102-106.
Song, J. J., J. Liu, et al. (2003). "The crystal structure of the Argonaute2 PAZ domain reveals an RNA binding motif in RNAi effector complexes." Nat Struct Biol 10(12):1026-1032.
Song, J. J., S. K. Smith, et al. (2004). "Crystal structure of Argonaute and its implications for RISC slicer activity." Science 305(5689):1434-1437.
Stevens, J., O. Blixt, et al. (2006). "Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus." Science 312(5772):404-410.
Straub, J. E. and D. Thirumalai (1993). "Theoretical probes of conformational fluctuations in S-peptide and RNase A/3'-UMP enzyme product complex." Proteins 15:360-373.
Suzuki, Y. (2004). "New methods for detecting positive selection at single amino acid sites." J Mol Evol 59(1):11-19.
Suzuki, Y. and T. Gojobori (1999). "A method for detecting positive selection at single amino acid sites." Mol Biol Evol 16(10):1315-1328.
Szittya, G., Molnar A, et al. (2002). "Short defective interfering RNAs of tombusviruses are not targeted but trigger post-transcriptional gene silencing against their helper virus." Plant Cell 14:1-15.
Tamura, K., J. Dudley, et al. (2007). "MEGA4:Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0." Mol Biol Evol 24(8):1596-1599.
Thorpe, I. F. and C. L. Brooks Iii (2007). "Molecular evolution of affinity and flexibility in the immune system." Proc Natl Acad Sci U S A 104(21):8821.
Thrope, I. F. and C. L. Brooks (2007). "Molecular evolution of affinity and flexibility in the immune system." Proc. Natl. Acad. Sci.104:8821-8826.
Tirado-Rives, J. and W. L. Jorgensen (2006). "Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding." J Med Chem 49: 5880-5884
Tomari, Y. and P. D. Zamore (2005). "Perspective:machines for RNAi." Gene Dev 19(5):517-529.
Tucker, M. J., R. Oyola, et al. (2006). "A Novel Fluorescent Probe for Protein Binding and Folding Studies:P-Cyano-Phenylalanine." Biopolymers 83:571-576.
van Nimwegen, E. (2006). "Epidemiology. Influenza escapes immunity along neutral networks." Science 314(5807):1884-1886.
Vargason, J. M., G. Szittya, et al. (2003). "Size selective recognition of siRNA by an RNA silencing suppressor." Cell 115(7):799-811.
Verdel, A. and D. Moazed (2005). "RNAi-directed assembly of heterochromatin in fission yeast." Febs Lett 579(26):5872-5878.
Vionnet, O., Y. M. Pinto, et al. (1999). "Suppression of gene silencing:a general strategy used by diverse DNA and RNA viruses of plants." Proc. Natl Acad. Sci. USA 96:14147-14152.
Voinnet, O. (2001). "RNA silencing as a plant immune system against viruses." Trends Genet 17(8):449-459.
Voinnet, O. (2005). "Induction and suppression of RNA silencing:insights from viral infections." Nature Rev. Genetics 6:206-220.
Wang, Y, S. Juranek, et al. (2008). "Structure of an argonaute silencing complex with a seed-containing guide DNA and target RNA duplex." Nature 456(7224):921-926.
Wang, Y., S. Juranek, et al. (2009). "Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes." Nature 461(7265):754-761.
Wang, Y., G. Sheng, et al. (2008). "Structure of the guide-strand-containing argonaute silencing complex." Nature 456(7219):209-213.
Warshel, A. (1984). "Simulating the Energetics and Dynamics of Enzymatic Reactions " in Specificity in Biological Interactions, Pontificiae Academiae Scientiarum Scripta Varia 55:60-81.
Warshel, A., P. K. Sharma, et al. (2006). "Modeling Electrostatic Effects in Proteins,,1764 (11), 1647-1676." Biochim. Biophys. Acta 1764(11):1647-1676.
Warshel, S. L. a. A. (1968). "A Consistent Force Field for Calculation of Conformations Vibrational Spectra and Enthalpies of Cycloalkane and n-Alkane Molecules." J. Chem. Phys.49.
Webster, R. G., W. J. Bean, et al. (1992). "Evolution and ecology of influenza A viruses." Microbiol Rev 56(1):152-179.
Webster, R. G., W. G. Laver, et al. (1982). "Molecular mechanisms of variation in influenza viruses." Nature 296(5853):115-121.
Weis, W., J. H. Brown, et al. (1988). "Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid." Nature 333(6172):426-431.
Weis, W. I., A. T. Brunger, et al. (1990). "Refinement of the influenza virus hemagglutinin by simulated annealing." J Mol Biol 212(4):737-761.
Wightman, B., I. Ha, et al. (1993). "Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans." Cell 75(5):855-862.
Xia, Z., Z. Zhu, et al. (2009). "Recognition mechanism of siRNA by viral p19 suppressor of RNA silencing:a molecular dynamics study." Biophys J 96(5):1761-1769.
Yan, K. S., S. Yan, et al. (2003). "Structure and conserved RNA binding of the PAZ domain.' Nature 426(6965):468-474.
Yang, W., R. Bitetti-Putzer, et al. (2004). "Free energy simulations:use of reverse cumulative averaging to determine the equilibrated region and the time required for convergence." J Chem Phys 120(6):2618-2628.
Yang, Z., R. Nielsen, et al. (2000). "Codon-substitution models for heterogeneous selection pressure at amino acid sites." Genetics 155(1):431-449.
Yang, Z. and W. J. Swanson (2002). "Codon-substitution models to detect adaptive evolution that account for heterogeneous selective pressures among site classes." Mol Biol Evol 19(1):49-57.
Ye, K. Q., L. Malinina, et al. (2003). "Recognition of small interfering RNA by a viral suppressor of RNA silencing." Nature 426(6968):874-878.
Yuan, Y. R., Y. Pei, et al. (2005). "Crystal structure of A. aeolicus argonaute, a site-specific DNA-guided endoribonuclease, provides insights into RISC-mediated mRNA cleavage." Mol Cell 19(3):405-419.
Zhang, B., X. Pan, et al. (2006). "Plant microRNA:a small regulatory molecule with big impact." Dev Biol 289(1):3-16.
Zhou, R., P. Das, et al. (2008). "Single Mutation Induced H3N2 Hemagglutinin Antibody Neutralization:A Free Energy Perturbation Study." J. Phys. Chem. B 112:15813-15820.
Zhou, R. H., X. H. Huang, et al. (2004). "Hydrophobic collapse in multidomain protein folding." Science 305(5690):1605-1609.