Molecular Dynamics Simulations of Intrinsically Disordered Proteins: Force Field Evaluation and Comparison with Experiment
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- 作者：Jo茫o Henriques ; Carolina Cragnell ; Marie Skep枚
- 刊名：Journal of Chemical Theory and Computation
- 出版年：2015
- 出版时间：July 14, 2015
- 年：2015
- 卷：11
- 期：7
- 页码：3420-3431
- 全文大小：634K
- ISSN：1549-9626
文摘
An increasing number of studies using molecular dynamics (monospace">MD) simulations of unfolded and intrinsically disordered proteins (monospace">IDPs) suggest that current force fields sample conformations that are overly collapsed. Here, we study the applicability of several state-of-the-art monospace">MD force fields, of the monospace">AMBER and monospace">monospace">GROMOS variety, for the simulation of Histatin 5, a short (24 residues) cationic salivary monospace">IDP with antimicrobial and antifungal properties. The quality of the simulations is assessed in three complementary analyses: (i) protein shape and size comparison with recent experimental small-angle X-ray scattering data; (ii) secondary structure prediction; (iii) energy landscape exploration and conformational class analysis. Our results show that, indeed, standard force fields sample conformations that are too compact, being systematically unable to reproduce experimental evidence such as the scattering function, the shape of the protein as compared with the Kratky plot, and intrapeptide distances obtained through the pair distance distribution function, p(r). The consistency of this deviation suggests that the problem is not mainly due to protein鈥損rotein or water鈥搘ater interactions, whose parametrization varies the most between force fields and water models. In fact, as originally proposed in [Best et al. J. Chem. Theory Comput.ml:space="preserve"> 2014ml:space="preserve">, m>10 m>ml:space="preserve">, 5113ml:space="preserve">鈥?/x> 5124.], balanced protein鈥搘ater interactions may be the key to solving this problem. Our simulations using this approach produce results in very good agreement with experiment.