THEORETICAL STUDY OF PROTEIN FOLDING KINETICS

我们从氨基酸序列预测蛋白质构象的能力 这在很大程度上取决于对蛋白质如何折叠的理解。统计 蛋白质的力学理论现在已经发展到这样的地步 理解是触手可及的。我们建议发展一种蛋白质理论- 基于序列设计与折叠相结合的折叠动力学思想 在一个力场的框架内折叠模拟。这 使我们能够理清蛋白质科学的两个关键问题： **蛋白质折叠动力学的机制是什么？ **如何找到蛋白质折叠的正确平均力势能？ 我们的初步研究表明，这是一种现实的方法， 使我们能够回答以下问题。 1.研究褶皱的成核机制，即确定褶皱的位置 以及不同蛋白质(泛素、Bamase、 维林)。用实验预测和检验核位点的点突变 它们具有最明显的动力学含义。学习如何预测 从序列中折叠原子核。 2.研究核形成后的折叠路径 折叠过程对原生构象以及分布的影响 引起生物指数折叠的旁路“陷阱”的结构 运动学。预测的快速动力学相与实验结果的比较 观测到的速度和幅度。 3.将侧链包装包含到模型中，设计原生构象 具有紧密堆积的侧链，并获得折叠的完整描述 从随机卷曲通过熔化的球体到自然状态。

Our ability to predict conformation of proteins from amino acid sequences depends strongly on understanding of how proteins fold. Statistical mechanical theory of proteins has now progressed to the point that such understanding is within reach. We propose to develop a theory of protein- folding kinetic based on the idea of combining the sequence design and folding simulations within the framework of the one force-field. This allows us to disentangle the two key questions of protein science: * What is the mechanism of protein folding kinetics? * How to find the correct potential of mean force for protein folding? Our preliminary studies showed that this is a realistic approach which allowed us to address the following questions. 1. Study the nucleation mechanism of folding, i.e. determine the location and size of folding nuclei for different proteins (ubiquitin, bamase, villin). Predict and test experimentally point mutations in nucleus sites which have the most pronounced kinetic implications. Learn how to predict folding nucleus from sequence. 2. Study the pathway of folding which, after nucleus is formed, directs folding process to the native conformation as well as the distribution and structure of off-pathway "traps" which give rise to bioexponential folding kinetics. Compare predicted fast kinetic phases with experimentally observed rates and amplitudes. 3. Include side-chains packing into models, design native conformation with tightly packed side-chains and obtain complete description of folding from the random coil through molten globule to the native state.