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High Resolution Free Energy Landscape Analysis of Protein Folding Dynamics

蛋白质折叠动力学的高分辨率自由能景观分析

基本信息

批准号：
BB/J016055/1
负责人：
Sergey Krivov
金额：
$ 35.53万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FJ016055%2F1
关键词：
Resolution Free Energy Landscape Analysis

项目摘要

Understanding the mechanism by which proteins fold to their native state remains a problem of fundamental interest in biology, in spite of the fact that it has been studied for many years. Moreover, now that misfolding has been shown to be the source of a range of diseases, a knowledge of the factors that determine whether a polypeptide chain will fold to its native state or aggregate has become all the more important. While the field of protein folding generally is considered to be mature, much controversy still remains on many fundamental topics including the importance of residual structure in denatured states, the nature of folding steps and kinetic barriers as well the extent of pathway diversity. These questions can be analysed in a rigorous way by describing the folding dynamics as diffusion on a free energy landscape. However, in spite of their fundamental importance the quantitatively accurate free energy landscapes of proteins are yet to be determined. The state of the art experimental techniques lack the necessary spatial and temporal resolution. Properties of the landscapes can be probed only indirectly. Simulation, in principle, can provide (infinitely) high spatial and temporal resolution, necessary for the construction of the quantitatively accurate free energy landscapes. Recently, due to advances in the hardware and simulation methodology realistic simulation of folding of small fast-folding proteins became computationally affordable. The current record holder is the simulation reported in the landmark paper by Shaw et al. The paper presents a ``brute-force'' 200 $\mu$s detailed all-atom equilibrium folding simulation of FIP35 protein in explicit water that contains 15 folding-unfolding events with the folding rate and the native structure in agreement with experiment. Many more simulations are now in progress. Which opens a new exciting era, when a detailed understanding of the controversial issues surrounding protein folding dynamics becomes possible. The trajectories obtained in such simulations, which contain the detailed information about the folding dynamics, are many terabytes in size and generally present a big challenge for an automated analysis. Moreover, accurate quantitative analysis of protein folding dynamics in terms of free energy landscapes is notoriously difficult. Conventional approaches, even though being based on solid physical intuition, often lead to suboptimal results with simple free energy landscapes which hide the inherent complexity of folding dynamics. Such landscapes, in essence, through away the biggest advantage of the simulation - the wealth of detailed information. We will apply the newly developed rigorous approach to determine high-resolution quantitatively accurate free energy landscape for protein folding. Later the approach will be extended to determine such landscape based on trajectories recorded in single molecule experiments.

了解蛋白质折叠到其天然状态的机制仍然是生物学中的一个基本问题，尽管它已经研究了多年。此外，既然错误折叠已被证明是一系列疾病的根源，那么了解决定多肽链是否折叠成其天然状态或聚集体的因素就变得更加重要。虽然蛋白质折叠的领域一般被认为是成熟的，许多争议仍然存在许多基本的主题，包括在变性状态下的残余结构的重要性，折叠步骤和动力学障碍的性质以及途径的多样性程度。这些问题可以通过将折叠动力学描述为自由能景观上的扩散来严格分析。然而，尽管其基本的重要性，定量准确的自由能景观的蛋白质尚未确定。最先进的实验技术缺乏必要的空间和时间分辨率。景观的性质只能间接地探测。模拟，在原则上，可以提供（无限）高的空间和时间分辨率，必要的定量准确的自由能景观建设。最近，由于硬件和模拟方法的进步，小的快速折叠蛋白质的折叠的逼真模拟变得计算负担得起。目前的记录保持器是Shaw等人在里程碑式的论文中报道的模拟。该论文提出了一个“蛮力”200 $\mu$s详细的FIP 35蛋白在显式水中的全原子平衡折叠模拟，其中包含15个折叠-去折叠事件，折叠速率和天然结构与实验一致。更多的模拟正在进行中。这开启了一个新的令人兴奋的时代，当详细了解围绕蛋白质折叠动力学的争议问题成为可能。在这种模拟中获得的轨迹包含有关折叠动力学的详细信息，其大小为许多TB，通常对自动分析提出了很大的挑战。此外，精确的定量分析蛋白质折叠动力学的自由能景观是出了名的困难。传统的方法，即使是基于坚实的物理直觉，往往导致次优的结果与简单的自由能景观隐藏的内在复杂性折叠动力学。这样的景观，从本质上讲，通过模拟走了最大的优势--丰富的详细信息.我们将应用新开发的严格的方法来确定高分辨率定量准确的蛋白质折叠的自由能景观。稍后，该方法将被扩展到基于单分子实验中记录的轨迹来确定这样的景观。