Research

Our research falls into the following main areas:

1) Development of weighted ensemble path sampling strategies and software (WESTPA) for efficient sampling of rare events with rigorous kinetics.
2) Application of simulations to characterize mechanisms of protein conformational transitions, binding, and assembly processes.
3) Development of simulation strategies for rational enhancement of kinetics for engineered protein conformational switches.
4) Development of implicitly polarized force fields (AMBER ff15ipq/ff15ipq-m) for canonical proteins and protein mimetics.

Our work is featured here by the University of Pittsburgh’s Center for Research and Computing.

2020 Gordon Bell Special Prize Recipients

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) - design of protein conformational switches
Angela Gronenborn (University of Pittsburgh) - integrative structural biology
Sunil Saxena (University of Pittsburgh) - integration of 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. Movie of a 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. Movie of 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. Movie of 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. Movie of 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. Movie of 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.