Prediction of the Quaternary Structure and Folding Thermodynamics of Multimeric Helical Proteins

斯科尔尼克，JMCB 9986019这项研究的长期目标是开发能够预测小分子寡聚螺旋蛋白质的四级结构并提供对其热力学性质的定性见解的算法。为了实现这些目标，Skolnick和Kolinski发展的晶格模型将被重新参数化以更好地再现二级和三级相互作用的平衡，变性状态属性将被模拟以确保它们得到适当的处理，并将预测简单的多聚体螺旋蛋白质的四级结构和折叠热力学。特别是，利用熵采样蒙特卡罗方法，将研究螺旋线圈的四级结构，如Gcn4亮氨酸拉链、ITS片段、Hodges设计的序列和基于ROP的二聚体。许多蛋白质只有在与多聚体结合时才具有生物活性。例如，真核基因调控蛋白中存在的亮氨酸拉链基序是调控蛋白识别和结合DNA的三种已知模式之一。显然，预测它们的四级结构的能力具有实际意义。与大量的实验工作相比，关于这些重要系统的理论研究很少。这里描述的研究旨在解决螺旋线圈和一些更复杂的多聚体螺旋蛋白，如ROP的这一需求。这些研究是了解代谢和信号通路的分子水平的第一步。该项目由分子和细胞生物科学部的分子生物物理学计划和化学部的理论物理化学计划共同支持。

Skolnick, JMCB 9986019 The long-term objectives of this research are the development of algorithms capable of predicting the quaternary structure of small oligomeric helical proteins as well as to provide qualitative insights into their thermodynamic properties. To accomplish these goals, the lattice models developed by Skolnick and Kolinski will be reparameterized to better reproduce the balance of secondary and tertiary interactions, denatured state properties will be simulated to insure that they are treated appropriately, and the quaternary structure and folding thermodynamics of simple, multimeric helical proteins will be predicted. In particular, using Entropy Sampling Monte Carlo, the quaternary structures of coiled coils such as the GCN4 leucine zipper, its fragments, sequences designed by Hodges, and ROP-based dimers will be examined.Many proteins only assume their biologically active conformation on association to multimers. For example, the leucine zipper motif present in eukaryotic gene regulatory proteins is one of the three known modes by which regulatory proteins recognize and bind DNA. Obviously, the ability to predict their quaternary structure is of practical importance. In contrast to the substantial body of experimental work, there are few theoretical studies on these important systems. The research described here is aimed at addressing this need in coiled coils and in somewhat more complicated multimeric helical proteins, such as ROP. Such studies are the first steps in the understanding on a molecular level of metabolic and signaling pathways.This project is jointly supported by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Theoretical Physical Chemistry Program in the Division of Chemistry.