Research

Our research centers on four main areas:

1) Advancing weighted ensemble path sampling strategies and software (WESTPA) for efficient sampling of rare events with rigorous kinetics.
2) Developing implicitly polarized AMBER force fields for both canonical proteins and protein mimetics.
3) Conducting molecular simulations to investigate pathways and kinetics of complex processes, including large-scale protein conformational transitions, protein-ligand (un)binding, and chemical reactions.
4) Designing computational strategies to rationally enhance the kinetics of engineered protein conformational switches.

During the pandemic, we were part of an international team that received the 2020 Gordon Bell Special Prize for COVID-19 Research - often referred to as the “Nobel Prize in Supercomputing”. Our WESTPA-generated movies capturing the coronavirus spike opening process were featured on the front page of the New York Times, December 1, 2021. This work was also highlighted by PittWire.

Collaborations:

With computational labs:

Daniel Zuckerman (Oregon Health and Science University) - weighted ensemble strategies
David Case (Rutgers University) - implicitly polarized force fields
Rommie Amaro (University of California, San Diego) - coronavirus applications
Arvind Ramanathan (Argonne National Lab) - deep-learning enhanced weighted ensemble strategies

With experimental labs:

Kevin Gardner (CUNY Advanced Science Research Center) - exploiting buried cavities for drug discovery
Stewart Loh (SUNY Upstate Medical University) - designing protein conformational switches
Angela Gronenborn (University of Pittsburgh) - integrating simulations with NMR
Sunil Saxena (University of Pittsburgh) - integrating simulations with magnetic resonance restraints
Seth Horne (University of Pittsburgh) - folding mechanisms of protein mimetics

Movie Highlights:

Azide clock reaction simulated with QM/MM molecular dynamics. A complete chemical reaction pathway revealing azide “crawling” along the “propeller” phenyl-rings of the 4-OCH3-T+ trityl cation. Our study demonstrates the importance of examining such dynamical effects, which explain differences in kinetics for a series of azide-clock reactions.

A glycan gate controls opening of the SARS-CoV-2 spike protein. The seconds-timescale spike-opening process of SARS-CoV-2 (1M atom system), as simulated using the weighted ensemble strategy. The glycan gate at the N288 position is highlighted in magenta.

Protein-protein binding pathways and kinetics from explicit-solvent simulations. A binding pathway for barnase (blue) and barstar (orange) from a weighted ensemble simulation. Residues at the binding interfaces of barnase (S38 and R59) and barstar (D35, D39, and W44) are highlighted in cyan and yellow, respectively. This simulation can be completed within 10 days using 16 modern GPUs. “The Story Unfolds” music by Jingle Punks is royalty-free.

First atomistic simulations of protein-peptide binding pathways to yield an on-rate. A coupled folding and binding pathway generated by weighted ensemble simulations involving a disordered p53 peptide (gold) and MDM2 protein (gray). “Anchor” residues which become the most buried upon binding are highlighted in red, blue, and green for F19, W23, and L26, respectively.

Large enhancement in protein switching kinetics by computational design. A protein-based calcium sensor, switching from an “on” state with fluorophores (yellow spheres) far apart to an “off” state (fluorophores adjacent). Our results predicted mutations that enhanced switching kinetics by >32-fold. Guitar music for this work was composed and performed by Alex J. DeGrave, and is freely available for reuse under a CC BY 4.0 license.

Shifts in the beta-sheet register of a protein-peptide complex. Based on our conventional simulations in explicit solvent, rearrangement of a misregistered β-sheet involving a peptide fragment of the hNIFK signaling protein (yellow) and the complementary β-strand of the FHA domain receptor of the Ki67 cancer marker protein (cyan) occurs via an “aromatic crawling” mechanism in which the anchoring of peptide residue F263 into a transient hydrophobic pocket of the receptor appears to facilitate rearrangement to the native state with the intended beta-sheet register.

Domain swapping of an engineered two-domain protein switch. The two domains are barnase (shades of blue) and ubiquitin (shades of red). In this conventional molecular simulation, domain swapping involves the less stable domain, barnase, in which intermolecular folding occurs between the barnase domains of two different molecules.