Collaborative Research: Mapping protein-membrane interactions from molecules to cell-level dynamics

点击翻译按钮获取中文摘要

Biological membranes that surround the cell, and organelles within the cell, are complex mixtures of proteins and phospholipids, distinct classes of biological molecules which combine to seal off the cell and its compartments. How proteins and phospholipids work together to enable the processes that must work across these barriers is not well understood. The project will investigate the interwoven dynamics coupling cellular membrane shape with embedded protein orientations and aggregation. The research will explore the role of membrane-mediated protein aggregations in the clustering of viral coat proteins that facilitates the entry and exit of viral particles (e.g., Covid and influenza) from cells, the activation of membrane channels in processes like touch sensation, and the involvement of membrane proteins in the creation of mitochondrial membrane shape, which aids in maximizing cellular energy production. Answers to these questions can lead to novel therapeutics for viruses and to a deeper understanding of cell physiology. The project will specifically lead to a mapping from the structure and composition of individual proteins to the large-scale motions of the membranes in which they are embedded, providing a general physics-based understanding of cellular membrane processes. The research will form a foundation for interdisciplinary graduate student training and as a foundation for outreach to STEM undergraduates and K12 students in the Tucson and San Francisco areas. Constructing models that properly describe how atomic level interactions lead to mesoscale membrane distortions poses a grand challenge. The research proposed here meets this challenge using a multiscale approach to develop chemically accurate descriptions of the interaction between integral membrane proteins and the surrounding membrane that is then feed upwards to create a realistic continuum model of protein-driven membrane morphology at the cell level. The project will use molecular dynamics simulations to determine the interaction of a single protein with a membrane and how small groups of proteins interact and deform membranes. These simulations will be carried out on a set of proteins with distinct geometric and chemical properties. The results from these simulations will then be used to parameterize a continuum level model of protein-membrane interactions that will be used to explore the cell-level membrane dynamics involved in viral pathogenesis, mitochondrial morphogenesis, and PIEZO channels in mechanosensation. The algorithms that are developed will be applicable to a range of problems in the dynamics of surfaces, thereby impacting research in biology, biomedical science, physics, and engineering and will be made freely-available to the community. The training that is proposed will support students and postdocs in a broadly interdisciplinary research plan that crosses multiple length scales and spans molecular biology and cellular biophysics.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.