Dilip Asthagiri

The persistent challenge of liquid water and macromolecular hydration thermodynamics

Abstract:

Biology rests on the physical and chemical behavior of macromolecules and their complexes in the liquid water matrix. Understanding the molecular basis of biological processes therefore requires understanding the solution thermodynamics of macromolecules. For much the history of protein science, this solution thermodynamics has been interpreted on the basis of small molecule analogues of groups comprising the protein. This group-additive approach still underlies much of our current understanding of proteins in solution, including how we rationalize their stability and phase behavior, their response to mutations, and their interactions with small molecules such as drugs. Advances over the last decade and a half in statistical mechanical theory, allied algorithms, and computational power have now enabled the solution thermodynamics of soluble proteins to be evaluated using all-atom simulations by treating all protein groups holistically within a unified framework. I will discuss this development and the insights it has yielded, including in encouraging a shift away from textbook accounts of factors determining protein folding and assembly and toward a picture that assigns the solvent a far richer role.

Simulations of liquid water in biological systems commonly freeze bond-vibration and angle-bending modes. As computing power grows, molecular dynamics simulations are pursuing ever larger systems over ever longer time scales, often using large integration time steps to do so. I will discuss how these large time steps cause a breakdown of equipartition, and how this breakdown, in turn, affects the phase behavior of the simulated liquid and alters the hydration thermodynamics of a model polypeptide.

Speaker: Dilip Asthagiri, Oak Ridge National Labs

Dilip Asthagiri is a Senior Staff Scientist working in Computational Biomedicine within the National Center for Computational Sciences at ORNL. He joined ORNL in August 2022. Prior to ORNL he was an Associate Research Professor and Director of the MChE Program at Rice University. Dilip received his doctorate from the University of Delaware (1999), Master's from the University of Michigan (1994), and Bachelor's from the Indian Institute of Technology-Madras (1992), all in chemical engineering. His previous appointments include Visiting Scientist at the University of Texas Medical Branch, Assistant Professor at the Johns Hopkins University, and Technical Staff Member at the Los Alamos National Laboratory. His research interests are in molecular thermodynamics and statistical mechanics of liquids and bio-macromolecules, NMR relaxation, metal chelation for MRI contrast agents, and multi-scale computer simulations.

Host: Srini Raghavan

Seminars start at 4:00 pm, and refreshments will be served at 3:45 pm. All seminars are held in the 2136 Physical Sciences Complex (#415) unless otherwise noted.