Development of Generalized-Ensemble Algorithms and their Application in Protein Studies

俄克拉荷马大学的乌尔里希·汉斯曼得到了化学系化学理论、模型和计算方法计划的支持，旨在开发理论和计算方法，旨在克服广义系综和复制交换技术在蛋白质折叠研究中的局限性。为此，重新制定了副本交换协议，以使其能够在多尺度和显式溶剂模拟中有效使用；并建立了一个自动程序，用于设计最大限度地采样折叠/展开转变的系综。这些技术随后被用来探索多漏斗概念的用途，以描述突变、环境变化或与其他分子相互作用对蛋白质折叠的作用。为此，我们研究了突变引起的蛋白G的A和B结构域折叠格局的变化以及两种功能形式的淋巴肌动蛋白之间的相互转化。该项目旨在克服采样困难，这些困难阻碍了原子分子动力学或蒙特卡罗模拟在探索细胞分子机制方面补充实验的使用。为了更全面地了解蛋白质的折叠和细胞过程，人们开发和应用了新的技术来研究特别有趣的蛋白质的折叠机制。为了扩大该项目的影响，组织了一次“从计算生物物理学到系统生物学”的年度讲习班；并为不同背景的本科生提供暑期实习。

Ulrich Hansmann of the University of Oklahoma is supported by the Chemical Theory, Models and Computational Methods program in the Chemistry Division to develop theoretical and computational approaches aimed at overcoming limitations of generalized-ensemble and replica-exchange techniques in protein folding studies. For this purpose, the replica exchange protocol is reformulated to enable its efficient use in multiscale and explicit solvent simulations; and an automatic procedure is established for designing ensembles that maximize the sampling of folding/unfolding transitions. These techniques are then used to explore the utility of a multi-funnel concept for describing the role of mutations, changes in environment, or interaction with other molecules on protein folding. For this purpose, mutation-induced changes in the folding landscape of the A and B domain of protein G and the inter-conversion between the two functional forms of lymphotactin are studied. The project aims at overcoming sampling difficulties that hold back the use of atomistic molecular dynamics or Monte Carlo simulations for complementing experiments in exploring the molecular machinery of cells. New techniques are developed and applied to study the folding mechanism of especially interesting proteins, in order to obtain a more complete view of protein folding and cellular processes. In order to broaden the impact of the project an annual workshop "From Computational Biophysics to Systems Biology" is organized; and summer internships are offered to undergraduate students from diverse backgrounds.