September 3, 2016

Research

We work in the area of Theoretical and Computational Biophysical Chemistry, which aims to understand how biological systems work in terms of the fundamental laws of Physics and Chemistry. One goal of our research has been to understand the forces that operate within and between biomolecules and develop quantitative models for their energy as a function of conformation. One of the most difficult interactions to model is that between biomolecules and solvent. Many years ago we developed a model for this interaction (EEF1) based on the idea that solute atoms exclude solvent from the region they occupy. We then extended this “implicit solvent” model to biological membranes, which are essentially a heterogeneous solvent. This allowed us to study the folding and stability of membrane proteins, a class of proteins of extraordinary importance. It has also allowed us to study the interaction of peptides and soluble proteins with membranes, which is implicated in many biological processes such as membrane fusion, innate immunity, or signal transduction.

One problem we have focused on in the past several years is the mechanism of peptide-induced pore formation in biological membranes. Many of these pore-forming peptides are naturally produced by a wide range of organism as a defense against bacterial infection. We are employing both implicit solvent and explicit solvent molecular dynamics simulations to characterize the pore structures and the sequence-activity relationships of these antimicrobial peptides. We are also exploring the hypothesis that degenerative diseases, such as Alzheimer’s, Parkinson’s, and type II diabetes, are caused by membrane permeabilization.

Another major new direction in the lab is the development of classical molecular dynamics simulations that account for the ability of protons to “hop” between water molecules or between amino acid side chains. This will allow us to study the mechanism of proton conduction in proton channels and other membrane proteins that use the movement of protons to perform useful work, such as solute transport against its gradient or ATP synthesis.

More information on specific projects:

Implicit solvent modeling of protein-membrane interactions
Antimicrobial Peptides
Peripheral Membrane Proteins
Classical molecular dynamics simulations with mobile protons