Mimicking the secondary structures of proteins and peptides to modulate Protein-Protein Interactions

人类基因组编码大约20,000种不同的蛋白质，创造了一个巨大的潜在蛋白质-蛋白质相互作用（PPI）网络，这只是部分表征。蛋白质-蛋白质相互作用组（涉及PPIs的网络）是细胞内通路的核心，并决定任何给定蛋白质在生理上的作用。这种PPI的调节有望揭示生物系统内的关键分子机制，对理解蛋白质如何执行细胞功能至关重要。该计划的核心是开发拟肽分子，即能够模仿肽结构的分子，同时有利地调整其不需要的特性，并利用计算科学来分析这种支架的动力学并优先合成化合物。1. 基于多样性的热点富集PPI抑制剂文库的合成对PPI进行细致的解剖分析，可以表征参与识别的分子特征。我们将利用最近的发现和我们在固相支持合成方面的专业知识来开发一个新型肽类PPI调节剂库，旨在将相同的分子识别元件作为热点中过度代表的侧链。这些元件将被放置在支架上，为PPI提供合适的化学空间和形状，这些化学空间富含已知PPI抑制剂中过多的分子识别元件。我们进行了彻底的硅分析，以产生一类在拓扑和分子描述符方面具有适当特征的化合物2。基于三维预测方法的PPI界面二级结构的合理设计与合成。结构生物学的最新进展现在使我们能够在分子水平上阐明复杂大分子组装的结构，并表征蛋白质之间的相互作用界面。利用我们团队最近开发的一种结合分子动力学、独立成分分析（tICA）和高斯混合隐马尔可夫模型（GM HMM）的创新和强大的三维构象预测方法，我们将合理地设计和合成模拟两种感兴趣蛋白质之一的PPI界面的表位和二级结构。与标准HTS库相比，这个化学、生物学和计算科学交叉的多学科研究项目有望在PPI目标上提供更高的命中率。计算科学和实验评估协会将提供获得高选择性和高效PPI调制器所需的关键相互作用的见解。文库有望成为一套万能的化学生物学工具，用于表型分析，以破译关键的PPI通路。

The human genome encodes for approximately 20,000 different proteins creating a vast network of potential protein-protein interactions (PPI), which is only partially characterized. The protein-protein interactome (network involving PPIs) is central to intracellular pathways and determines any given protein's role in physiology. Modulation of such PPI promises to shed light on the key molecular mechanisms within a biological system and is crucial to understanding how proteins perform cellular functions. At the heart of the program is the development of peptidomimetic molecules, i.e., molecules capable of mimicking the structure of peptides while advantageously adjusting their undesirable properties and the exploitation of computational sciences to analyze the dynamics of such scaffolds and to prioritize compounds to synthesize. 1. Diversity-oriented synthesis of hot-spot enriched PPI inhibitor library Meticulous analysis of the anatomy of PPIs has allowed to characterize the molecular features involved in recognition. We will take advantage of recent findings and our expertise in solid phase-support synthesis to develop a library of novel peptidomimetic PPI modulators designed to expose the same molecular recognition elements as over-represented side chains in hot-spots. These elements will be on scaffolds that provide a chemical space and shape appropriate for the PPI chemical space enriched with molecular recognition elements over-abundant in known PPI inhibitors. We performed a thorough in silico analysis to produce a class of compounds that possess the proper profile in terms of topology and molecular descriptors 2. Rational design and synthesis of secondary structures at PPI interface using 3D prediction approach. Recent advances in structural biology now allow us to elucidate, at the molecular level, the structure of complex macromolecular assemblies and characterize the interactions interface between proteins. Using an innovative and powerful 3D conformation prediction approach combining molecular dynamics, independent component analysis (tICA), and a Gaussian Mixture Hidden Markov Model (GM HMM) recently developed in our group, we will rationally design and synthesize epitope and secondary structures at PPI interfaces mimicking one of the two proteins of interest. This multidisciplinary research program at the interface of chemistry, biology, and computational science is expected to give superior hit rates compared to standard HTS libraries on PPI targets. Association of computational sciences and experimental evaluation will provide insights on the key interactions needed to access highly selective and efficient PPI modulators. Libraries are expected to become a versatile chemical biology set of tools used in phenotypic assays to decipher critical PPI pathways.