The Application of Ligand-Mapping Molecular Dynamics Simulations to the Rational Design of Peptidic Modulators of Protein鈥揚rotein Interactions

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• 作者：Yaw Sing Tan ; David R. Spring ; Chris Abell ; Chandra S. Verma
• 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：3199-3210
• 全文大小：625K
• ISSN：1549-9626

文摘

A computational ligand-mapping approach to detect protein surface pockets that interact with hydrophobic moieties is presented. In this method, we incorporated benzene molecules into explicit solvent molecular dynamics simulations of various protein targets. The benzene molecules successfully identified the binding locations of hydrophobic hot-spot residues and all-hydrocarbon cross-links from known peptidic ligands. They also unveiled cryptic binding sites that are occluded by side chains and the protein backbone. Our results demonstrate that ligand-mapping molecular dynamics simulations hold immense promise to guide the rational design of peptidic modulators of protein鈥損rotein interactions, including that of stapled peptides, which show promise as an exciting new class of cell-penetrating therapeutic molecules.