Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy.
Methods Mol Biol. 2023;2705:113-133. doi: 10.1007/978-1-0716-3393-9_7.
Many biological functions are mediated by protein-protein interactions (PPIs), often involving specific structural modules, such as SH2 domains. Inhibition of PPIs is a pharmaceutical strategy of growing importance. However, a major challenge in the design of PPI inhibitors is the large interface involved in these interactions, which, in many cases, makes inhibition by small organic molecules ineffective. Peptides, which cover a wide range of dimensions and can be opportunely designed to mimic protein sequences at PPI interfaces, represent a valuable alternative to small molecules. Computational techniques able to predict the binding affinity of peptides for the target domain or protein represent a crucial stage in the workflow for the design of peptide-based drugs. This chapter describes a protocol to obtain the potential of mean force (PMF) for peptide-SH2 domain binding, starting from umbrella sampling (US) molecular dynamics (MD) simulations. The PMF profiles can be effectively used to predict the relative standard binding free energies of different peptide sequences.
许多生物功能是由蛋白质-蛋白质相互作用（PPIs）介导的，这些相互作用通常涉及特定的结构模块，如 SH2 结构域。抑制 PPIs 是一种日益重要的药物研发策略。然而，在设计 PPI 抑制剂时，一个主要的挑战是这些相互作用涉及到的大界面，在许多情况下，这使得小分子的抑制作用无效。肽是一种很有价值的小分子替代品，它的尺寸范围很广，可以有针对性地设计，以模拟 PPI 界面处的蛋白质序列。能够预测肽与靶结构域或蛋白质结合亲和力的计算技术是设计基于肽的药物工作流程中的一个关键阶段。本章描述了一种从伞状采样（US）分子动力学（MD）模拟开始，获得肽-SH2 结构域结合的平均力势（PMF）的方案。PMF 曲线可有效用于预测不同肽序列的相对标准结合自由能。
