Effects of the Cellular Environment of Protein Assembly

这个项目提出了一个多尺度的计算方法来研究环境对蛋白质折叠和聚集的影响。在体内，蛋白质在密集的环境中折叠，界面丰富（从膜到由其他生物分子产生的表面），并且存在许多可以充当拥挤剂的物质。 拥挤和表面效应都可以显著改变蛋白质折叠机制，并影响聚集途径。 表面在与生物材料和生物技术应用相关的聚集过程中起着同样重要的作用。PI将使用最先进的完全原子增强采样分子动力学模拟，再加上将在本项目的背景下开发的新的粗粒度模型的组合。 全原子模拟将集中在两个模型系统，胰岛淀粉样多肽和Tau蛋白的新结构。这些肽的折叠和早期聚集将在本体中研究，在不同程度的疏水性（从云母到石墨烯）的固体模型表面的存在下，并在生物学上重要的糖胺聚糖肝素的存在下。将开发新的粗粒度模型，以探索拥挤和表面（包括模型膜表面）对折叠和聚集的影响。由于粗粒度模型可以达到的时间和长度尺度远远超过使用完全原子模拟的时间和长度尺度，因此它们能够研究从单体折叠到完全纤维形成的整个聚集过程。本文提出的多尺度方法旨在阐明蛋白质在体内和体外折叠的基本原理，对蛋白质折叠和聚集的基本原理的深入理解将对生物技术和生物材料等学科产生重要影响。这项研究本质上是跨学科的，模拟结果将用于指导新的实验研究。在该项目背景下开发的所有计算模型和算法将免费向公众提供。PI积极参与指导科学领域代表性不足的群体（包括少数民族和妇女）和课程开发。PI参与当地圣巴巴拉小学儿童的化学外展活动，包括每周向五年级学生进行科学演示，以及每月的“科学之夜”活动。PI将通过引入新的演示模块和扩大该计划的范围，包括来自主要是西班牙裔学校的大量学生，扩大她对五年级学生的宣传。该项目由分子和细胞生物科学部的生物分子动力学，结构和功能集群以及物理学部的生命系统计划物理学共同支持。

This project presents a multiscale computational approach to studying the effects of the environment on protein folding and aggregation. In vivo, proteins fold in a dense environment, rich in interfaces (ranging from membranes to surfaces created by other biomolecules) and with a host of species present that can act as crowding agents. Both crowding and surface effects can dramatically alter protein folding mechanisms as well as affect aggregation pathways. Surfaces play an equally important role in aggregation processes related to biomaterial and biotechnological applications. The PI will use a combination of state of the art fully atomic enhanced sampling molecular dynamics simulations, coupled with novel coarse-grained models that will be developed in the context of this project. The fully atomic simulations will focus on two model systems, the Islet Amyloid Polypeptide and a novel construct of the Tau protein. The folding and early aggregation of these peptides will be studied in the bulk, in the presence of solid model surfaces of different degrees of hydrophobicity (ranging from mica to graphene) and in the presence of the biologically important glycosaminoglycan heparin. Novel coarse-grained models will be developed to probe the effects of crowding and surfaces (including model membrane surfaces) on folding and aggregation. Because coarse-grained models can reach time and lengths scales that far exceed those accessible using fully atomic simulations, they enable the study of the entire aggregation process from monomer folding to full-fledged fibril formation. The proposed integrated multiscale approach aims at elucidating some of the fundamental principles that differentiate in vivo from in vitro folding.A deeper understanding of the fundamental principles governing protein folding and aggregation will have impacts in a number of disciplines ranging from biotechnology and biomaterials. The research is inherently interdisciplinary, and results from the simulations will be used to guide new experimental studies. All computational models and algorithms developed in the context of this project will be made freely available to the public. The PI is actively involved in the mentoring of under-represented groups in science (both minority and women) and in curricular developments. The PI is involved in chemistry outreach activities to local Santa Barbara elementary school children, including weekly science demonstrations to fifth grade students, as well as monthly "Science Night" events. The PI will expand her outreach to the fifth grade students by introducing new demonstration modules and by expanding the scope of the program to include a significant number of students stemming from primarily Hispanic schools. This project is jointly supported by the Biomolecular Dynamics, Structure and Function Cluster in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Physics Division.