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.
