Developing and applying new theoretical and computational methods to study complex condensed phase systems

Gregory A. Voth

Gregory A. Voth

Haig P. Papazian 
Distinguished Service Professor
Department of Chemistry
The University of Chicago
Google Scholar Page

The research in the Voth Group involves theoretical and computer simulation studies of biomolecular, condensed phase, quantum mechanical, and materials systems. One of our goals is to develop new theory to describe such problems across multiple, connected length and time scales. Another related goal is to develop and apply new computational methods, tied to our multiscale theory, that can explain and predict complex phenomena occurring in these systems. Our methods are developed, for example, to probe protein-protein self-assembly, membrane-protein interactions, biomolecular and liquid state charge transport, complex liquids, self-assembly, and energy conversion materials. Our research is also often carried out in close collaboration with leading experimentalists from around the world. 

Material for Download

A Modern Perspective on the Hydrated Excess Proton (aka "Hydronium") 

Multi-scale Coarse-graining (MS-CG) Force Matching (FM) code is now publicly available for download 

Research News

The Origin of Coupled Chloride and Proton Transport in a Cl/H+Antiporter

ClC-ec1, a Cl- /H+ antiporter, is critical for maintaining ion concentrations and PH gradients in bacteria in acidic environments. In this work, we computationally characterized the rate-limiting step of the overall proton transport process in ClC-ec1 and the essential mechanism of the Cl-/H+ coupling. We found that the highest barrier for PT is located at the deprotonation of E148, and this barrier is significantly reduced by the binding of Cl- in the central site, which displaces E148 and thereby facilitates its deprotonation.

Molecular Modeling and Assignment of IR Spectra of the Hydrated Excess Proton in Isotopically Dilute Water

We developed a mixed quantum-classical model for the vibrational spectroscopy of the excess proton in isotopically dilute water.  The model is useful for decomposing IR spectra into contributions from different aqueous proton configurations as validated by our experimental collaborator Andrei Tokmakoff (UChicago). We find that the shift from Eigen to Zundel-like configurations is distinguished by a decrease in the O—H transition frequency.

Acid Activation Mechanism of the Influenza A M2 Proton Channel

The influenza A M2 channel (AM2) transports protons into the influenza virus upon acid activation. MS-RMD simulations were performed to characterize the free energy profiles of the proton transport events in the M2 channel. Our results show that decreasing pH causes the Trp41 gate to open, which decreases the deprotonation barrier of the His37 tetrad. This leads to channel activation, which is characterized by increased proton conductance.

Transition-Tempered Metadynamics is a Promising Tool for Studying the Permeation of Drug-like Molecules through Membranes

The recently developed transition-tempered metadynamics (TTMetaD) has been proven to converge asymptotically without sacrificing exploration of the collective variable space in the early stages of simulations. We applied TTMetaD to study the permeation of drug-like molecules through a lipid bilayer to investigate its usefulness in medicinal chemistry. Compared to other enhanced sampling methods, TTMetaD is able to predict the most accurate and reliable estimate of the potential of mean force in the early stages of the simulations. We also show that using multiple randomly initialized replicas allows convergence analysis and provides an efficient means to converge the simulations in shorter wall times and CPU times.

How Curvature-Generating Proteins Build Scaffolds on Membrane Nanotubes

Bin/Amphiphysin/Rvs (BAR) domain proteins control the curvature of lipid membranes in endocytosis, trafficking, cell motility, and the formation of complex subcellular structures. By combining quantitative microscopy with analytical modeling, we demonstrate that a highly curved BAR protein endophilin nucleates its scaffolds at the ends of a membrane tube, unlike the weaker curving protein centaurin, which binds evenly along the tube’s length. Our work implies that local protein–membrane interactions can affect the specific localization of proteins on membrane-remodeling sites.

-Linear Aggregation of Proteins on the Membrane as a Prelude to Membrane Remodeling

We used coarse-grained molecular simulations to investigate the way N-BAR proteins interact with one another on the surface of the membrane and generate its curvature. We show a striking assembly of proteins into linear aggregates and meshes that not only helps in understanding how subsequent membrane remodeling may occur, but demonstrates a mechanism for their very rapid recruitment, crucial for e.g. synaptic transmission.

On the Representability Problem and the Physical Meaning of Coarse-Grained Models

We discuss the relationship between coarse-grained (CG) observables and the corresponding fine-grained (FG) or experimental observables in the framework of systematic bottom-up CG modeling. The importance of this issue is illustrated with a simple polymer system that has implications for the coarse-graining of intramolecular degrees of freedom.

Multiscale Simulations of Protein Facilitated Membrane Remodeling

Many crucial biological processes, such as cell division, protein trafficking, and cell signaling, involve large-scale membrane shape and topology changes that are facilitated by complex membrane-protein interactions. In this Review we discuss the recent advances of our group in multiscale computational approaches for studying protein-mediated large-scale membrane remodeling.

Multiscale Simulations Reveal Key Features of the Proton Pumping Mechanism in Cytochrome c Oxidase

We used MS-RMD simulations to characterize the free energy profiles of the proton transport events in the cytochrome c oxidase (CcO) that enable proton pumping and chemical reaction. Our results show that the transfer of both the pumped and chemical protons are thermodynamically driven by electron transfer, and explain how proton back leakage is avoided by kinetic gating.

 

Center for Multiscale Theory and SimulationThe James Franck InstituteInstitute for Biophysical DynamicsComputation Institute