Interfacial and osmolyte-induced modulation of protein folding, assembly and adhesion

蛋白质是生命的基本组成部分，在我们的身体中发挥着多种功能，从保护我们免受感染的抗体，到催化生化反应的酶。蛋白质的功能与蛋白质可以采用的构象(或形状)密切相关。这个项目寻求开发新的计算工具来探索表面和溶液条件如何影响蛋白质的结构和功能。这些模拟将指导设计一类用于生物材料应用的新型蛋白质，包括生物启发的湿式粘合剂和蛋白质支架。在本项目范围内开发的代码将免费提供。PI和她的团队正在积极参与推广活动，包括面向五年级学生的化学课程，开发将在圣巴巴拉动物园展示的与湿性粘连有关的动手模块，以及让未被充分代表的少数族裔高中生参与一个暑期研究项目。该项目的重点是内在无序多肽，这是一种可以呈现多种不同构象、采用瞬时二级结构并执行多种功能的蛋白质。由于缺乏天然折叠，它们也容易自组装成从纤维到凹凸体的各种结构。在这个项目中，将使用从从头算分子动力学到粗粒度模型的一系列模拟技术来探索模型内在无序多肽的结构、功能和组装。该项目将解决三个具体目标。第一个目标将集中在分子理解湿粘着，使用本质上无序的贻贝足部蛋白作为模型系统。PI将与生物黏附领域的领先实验小组密切合作，研究序列和表面组成如何影响黏附。这项研究将为开发一类新的生物启发多肽作为水下粘合剂奠定基础。在第二个目标中，PI将使用分子动力学模拟和Kirkwood-Buff溶液理论来确定渗透分子TMAO抵消渗透分子尿素的蛋白质变性效应的机制。在实验测量的基础上，建立并验证了TMAO/尿素相互作用的优化力场，并将其用于研究混合渗透分子对本质无序多肽聚集的影响。在第三个目标中，PI将开发新的混合动力学蒙特卡罗/分子动力学算法，将应用于纤维伸长的研究。该项目由分子和细胞生物科学部的分子生物物理学集群和物理系的生命系统物理计划联合资助。

Proteins are fundamental building blocks of life, serving a multitude of functions in our body, from antibodies protecting us from infection, to enzymes catalyzing biochemical reactions. Protein function is intimately tied to the conformations (or shapes) that proteins can adopt. This project seeks to develop new computational tools to probe how surfaces and solution conditions affect protein structure and function. These simulations will guide the design of a new class of proteins for biomaterial applications, including biologically-inspired wet adhesives and protein scaffolds. Codes developed in the context of this project will be made freely available. The PI and her group are actively engaged in outreach activities, including a chemistry program geared at 5th grade students, the development of hands-on modules related to wet-adhesion that will be presented at the Santa Barbara zoo, and the involvement of underrepresented minority high school students in a summer research program.The focus of this project is on intrinsically disordered peptides, a class of proteins that can take on a multitude of disparate conformations, adopt transient secondary structures, and carry out multiple functions. With their lack of a native fold, they are also prone to self-assemble into structures ranging from fibrils to coacervates. In this project, the structure, function and assembly of model intrinsically disordered peptides will be probed using a hierarchy of simulations techniques, from ab initio molecular dynamics to coarse-grained models. The project will address three specific aims. The first aim will focus on a molecular understanding of wet adhesion, using the intrinsically disordered mussel-foot protein as a model system. Working closely with leading experimental groups in the field of biological adhesion, the PI will investigate how sequence and surface composition affect adhesion. This research will lay the groundwork for the development of a new class of biologically inspired peptides that can serve as underwater adhesives. In a second aim, the PI will use molecular dynamics simulations and the Kirkwood-Buff theory of solutions to determine the mechanism by which the osmolyte TMAO counteracts the protein denaturing effects of the osmolyte urea. An optimized force field for TMAO/urea interactions will be developed and validated based on experimental measurements, and used to study the effects of mixed osmolytes on the aggregation of intrinsically disordered peptides. In a third aim, the PI will develop novel hybrid kinetic Monte Carlo/Molecular Dynamics algorithms that will be applied to the study of fibril elongation.This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Division of Physics.