THEORETICAL STUDY OF PROTEIN FOLDING KINETICS

我们从氨基酸序列预测蛋白质构象的能力 很大程度上取决于对蛋白质折叠方式的理解。统计 蛋白质的力学理论现在已经发展到这样的程度， 理解是触手可及的。我们建议发展一种蛋白质理论- 基于序列设计和 在一个力场的框架内进行折叠模拟。这 让我们解开了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平均力的正确势能？ 我们的初步研究表明，这是一种现实的方法， 使我们能够解决以下问题。 1.研究折叠的成核机制，即确定位置 和不同蛋白质（泛素，Bamase， villin）。预测和实验测试细胞核位点的点突变 其具有最显著的动力学含义。学习如何预测 从序列中折叠细胞核。 2.研究细胞核形成后， 折叠过程中的天然构象以及分布， 引起生物指数折叠的非途径“陷阱”结构 动力学比较预测的快速动力学阶段与实验 观察速率和振幅。 3.包括侧链包装到模型中，设计天然构象 具有紧密堆积的侧链，并获得折叠的完整描述 从无规卷曲通过熔融小球到自然状态。

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.