Topics in Protein and RNA Folding and Dynamics

德克萨斯大学奥斯汀分校的Devarajan Thirumalai教授将在化学系（CHE）的化学理论、模型和计算方法项目以及分子和细胞生物科学系（MCB）的分子生物物理学项目的支持下，研究蛋白质和RNA相互作用以控制许多生物物理过程的方式。除了包含生命蓝图的DNA之外，蛋白质和RNA在不同环境中所采用的不同形状和构象决定了无数的细胞活动。Thirumalai教授将开发新的计算方法来模拟决定无序蛋白质中液滴形成的分子因素，以及RNA分子（以前被认为只是被动的信息载体）自组织形成凝聚体的机制。Thirumalai教授还将致力于开发理论框架和模拟方法，以了解分子马达（在细胞中携带货物）在极地轨道上采取多重步骤的分子基础。这些研究有可能为生物物理学中相关的复杂生物大分子过程提供更高水平的分子理解。该研究项目将涉及培养跨学科研究领域的学生和博士后，并可能在化学和复杂生化系统研究的相关领域产生广泛影响。在这个项目中，Thirumalai研究团队将创建新的粗粒度模型和计算工具来研究(i)内在无序蛋白（IDPs）的构象集合，（ii） RNA折叠，以及（iii） kinesin马达的步进机制。研究小组将采用多尺度模拟来研究特定位点磷酸化对原纤维形成IDPs组装的影响，以及拥挤的细胞环境对蛋白质功能的影响。在RNA折叠方面，Thirumalai教授将开发计算工具来解释多价离子离子，结合多电解质理论，并描述核糖体RNA折叠的热力学和动力学。同样，将设计新的方法来理解阳离子驱动液滴形成的机制和低复杂性RNA序列的相关动力学。最后，将模拟kinesin在微管（MT）上的步进，以解决有关电机头部运动对称性的基本问题：分离的kinesin电机是否总是在一侧（对称行走）或在两侧（不对称行走）之间交替通过MT绑定的电机。为了回答这个问题和相关问题，将使用新的模型来模拟驱动蛋白在机器翻译上的多个步骤。在这些研究中开发的用于探索具有生物学重要性的复杂系统的软件将可供分发。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With support from the he Chemical Theory, Models and Computational Methods program in the Division of Chemistry (CHE) and the Molecular Biophysics program in the Division of Molecular and Cellular Biosciences (MCB), Professor Devarajan Thirumalai of the University of Texas at Austin will study the ways that proteins and RNA interact with each other to control a number of biophysical processes. In addition to DNA, which contains the blueprint of life, a myriad of cellular activities are determined by the diverse shapes and conformations that proteins and RNA adopt in different environments. Professor Thirumalai will develop new computational methods for simulating the molecular factors that determine droplet formation in disordered proteins and the mechanisms by which RNA molecules, previously thought to be merely passive carriers of informations, self-organize to form condensates. Professor Thirumalai will also work to develop both a theoretical framework and simulation methods to understand the molecular basis by which molecular motors, which carry cargo in cells, take multiple steps on polar tracks. These studies have the potential to provide a higher level of molecular understanding of complex biomacromolecular processes of relevance in biophysics. The research project will involve training students and postdoctoral fellows in interdisciplinary research areas, and will likely have broad impact in related areas in chemistry and the study of complex biochemical systems.In this project, the Thirumalai research team will create new coarse-grained models and computational tools to investigate (i) the conformational ensembles of intrinsically disordered proteins (IDPs), (ii) RNA folding, and (iii) the stepping mechanism of kinesin motors. The research team will employ multiscale simulations to investigate the effects of phosphorylation at specific sites on the assembly of fibril-forming IDPs along with the impact of crowded cellular environments on protein function. Regarding RNA folding, Professor Thirumalai will develop computational tools to account for multivalent ions ions, complimented by polyelectrolyte theories, and describe the thermodynamics and kinetics of folding of ribosomal RNAs. New methods to understand the mechanisms of cation-driven droplet formation and the associated dynamics in low complexity RNA sequences will likewise be devised. Finally, the stepping of kinesin on a microtubule (MT) will be simulated to address fundamental questions regarding the symmetry of the motor head motions: whether the detached kinesin motor passes the MT bound motor always on one side (symmetric walk) or alternates between two sides (asymmetric walk). In order to answer this and related questions, new models will be used to simulate multiple steps that kinesin takes on a MT. The software developed in these studies for exploring complex systems of biological importance will be made available for distribution.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.