Conformational dynamics, reaction coordinates, and time scale separation in biomolecular systems from the perspective of energy flows

University Of Illinois At Chicago, Chicago IL

Investigators

Abstract

Ao Ma of the University of Illinois at Chicago (UIC) is supported by an award from the Chemical Theory, Models and Computational Methods Program in the Division of Chemistry to develop new theoretical and computational methods for understanding the mechanisms by which the shape of a protein morphs over time, as it moves and interacts with other molecules in the cell. Conformational changes are key to protein function, and understanding complex protein dynamics is essential to developing design strategies for new drugs and mitigating the impact of genomic defects on human health. Standard molecular dynamical simulations provide fine-grained information on protein conformational changes at the atomic level, but systematic methods for deducing overall mechanisms from this detailed information are currently lacking. In this project, new methods are being developed to rigorously extract mechanisms of protein conformational change from simulation data, by examining the flow of energy in the system over time. These methods are being applied and tested in a series of increasingly complex systems ranging from small peptides, to proteins interacting with a small molecule (ligand), and proteins in solution. Computer programs developed for this project are being made available for public download. Professor Ma is providing research experiences for high school students through the Illinois Mathematics and Science Academy (IMSA) Student Inquiry and Research (SIR) program, to stimulate enthusiasm and interest in science and research. In addition to mentoring and educating students at UIC, a Hispanic-Serving institution, Professor Ma provides an annual summer research experience to local high school science teachers, through an ongoing UIC educational program. The objective of this work is to develop novel theoretical and computational methods for advancing understanding of functionally-important protein dynamics. Reaction coordinates and time scale separation are fundamental concepts crucial to understanding mechanisms of protein conformational dynamics. Important organizing principles that have emerged in recent years from studies of protein dynamics include collective variables, ligand-induced conformational change, and solvent slaving. This project is formalizing and unifying these concepts from the perspective of energy flows. The central hypothesis is that, among strongly coupled coordinates, energy flows from fast coordinates into slow ones during a protein conformational change. Thus, reaction coordinates correspond to preferred channels, each exhibiting a high degree of energy flow. There are three specific aims: 1) Understand the mechanism of how a collective variable as reaction coordinate emerges in an activated process; 2) identify the mechanistic factors that determine relative time scales of the motions of a ligand and its surrounding protein matrix; and 3) clarify the mechanistic factors that determine relative time scales of solute coordinates and collective solvent modes. These aims are being investigated through a succession of increasingly complex biochemical problems: deca-alanine in solution, conformational changes in solvated HIV-1 protease in the presence of an inhibitor, ligand interactions with rhodopsin and myoglobin, and the effect of amino acid point mutations on myoglobin kinetics. Code developed for this project is being made available for public download. Professor Ma is providing research experiences and project mentoring for local high school students, to stimulate enthusiasm and interest in science and research, and an annual summer research experience in his laboratory for high school science teachers, supported by an ongoing UIC educational program. The insights developed in this project are being integrated into graduate courses taught by Professor Ma as part of the PhD program in Bioinformatics at UIC, one of just a few such programs in the U.S.