Effects of the Cellular Environment of Protein Assembly

这个项目提出了一种多尺度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，具有丰富的界面(从膜到其他生物分子创造的表面)，并且存在大量可以充当拥挤剂的物种。拥挤和表面效应都可以极大地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发挥着同样重要的作用。PI将使用最先进的完全原子增强采样分子动力学模拟的组合，以及将在本项目背景下开发的新的粗粒度模型。全原子模拟将集中在两个模型系统上，胰岛淀粉样多肽和一种新的Tau蛋白结构。这些多肽的折叠和早期聚集将在不同程度疏水性的固体模型表面(从云母到石墨烯)和具有生物重要性的糖胺聚糖肝素的存在下进行整体研究。将开发新的粗粒度模型来探索拥挤和表面(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远远超过使用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整的纤维形成的整个聚集过程。提出的综合多尺度方法旨在阐明一些区别于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多个学科产生影响。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。在该项目范围内开发的所有计算模型和算法都将免费向公众提供。非政府组织积极参与指导科学方面代表性不足的群体(包括少数群体和妇女)和课程发展。国际学生联合会参与了面向当地圣巴巴拉小学生的化学外展活动，包括每周向五年级学生进行科学示范，以及每月举行的“科学之夜”活动。PI将通过引入新的演示模块并将该计划的范围扩大到包括大量主要来自西班牙裔学校的学生来扩大她对五年级学生的接触。该项目得到了分子和细胞生物科学部的生物分子动力学、结构和功能簇以及物理部的生命系统物理计划的共同支持。

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.