Research

Our research falls into the following main areas:

1) Development of weighted ensemble path sampling strategies and software for efficient sampling of rare events (e.g. protein folding and binding) with rigorous kinetics.
2) Application of molecular simulations to characterize mechanisms of protein conformational transitions, binding, and assembly processes.
3) Development of molecular simulation strategies for rational design of engineered protein conformational switches.
4) Development of biomolecular force fields.

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

2020 Gordon Bell Special Prize Recipients

Collaborations:

With other computational labs:

Daniel Zuckerman (Oregon Health and Science University) - weighted ensemble strategies
David Case (Rutgers University) - AMBER force field development

With experimental labs:

Angela Gronenborn (University of Pittsburgh) - integrative structural biology
Seth Horne (University of Pittsburgh) - Folding mechanisms of protein mimetics
Stewart Loh (SUNY Upstate Medical University) - design of protein conformational switches

Protein-protein binding pathways and calculations of rate constants using fully-continuous, explicit-solvent simulations. Movie of a representative trajectory for barnase (blue) and barstar (orange) by weighted ensemble simulation with conformations recorded every ps. Residues at the binding interfaces of barnase (S38 and R59) and barstar (D35, D39, and W44) are highlighted in cyan and yellow, respectively. Also shown in the movie are surrounding water molecules with Na+ and Cl- ions to yield the experimental ionic strength of 50 mM NaCl. The background music is “The Story Unfolds” by Jingle Punks and royalty-free.

Atomistic simulations of complete protein-peptide binding pathways with rigorous kinetics. A representative binding pathway generated by weighted ensemble simulations involving an intrinsically 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.

Molecular simulations of a protein-based calcium sensor switching from the “on” state (where fluorophores, represented as yellow spheres, are distant) to the “off” state (fluorophores adjacent). The simulations were generated using the weighted ensemble strategy and the probability p (statistical weight) of each snapshot along the pathway is indicated in the lower right hand corner. The 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 explicit-solvent simulations, 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 molecular simulation, domain swapping involves the less stable domain, barnase, in which intermolecular folding occurs between the barnase domains of two different molecules.