Paul C. Whitford

Professor and Director of Graduate Studies

Department of Physics
Center for Theoretical Biological Physics
Northeastern University
111 Dana Research Center
360 Huntington Ave.
Boston, Massachusetts 02115 (617) 373-2952

B.S. Physics 2003, Worcester Polytechnic Institute
Ph.D. Physics 2009, University of California-San Diego

Professional Positions
Director's Postdoctoral Fellow, 2009-2012, Los Alamos National Laboratory
Senior Scientist, 2012 Rice University
Assistant Professor, 2012-2018 Northeastern University
Associate Professor, 2018-2024 Northeastern University
Professor, 2024-current Northeastern University



Biophysics of Molecular Machines

Our group investigates the physical principles that facilitate large-scale functional dynamics in biomolecular assemblies. When adopting a physicists' approach to study a new problem, one initially starts with the simplest Hamiltonian possible and then includes perturbations to account for higher-order effects. For many questions, one may begin with the well known harmonic oscillator description, where a particular energetic basin is described as a quadratic function in a given coordinate space. For biomolecular dynamics, the lowest-order harmonic description would be obtained through normal mode analysis. While normal mode analysis is very useful for describing the fluctuations about a particular energetic basin, large-scale conformational rearrangements go beyond the limits of this approximation. To address this limitation, we have utilized extended NMA-based approaches to describe conformational rearrangements, though they are not always reliable indicators of configurational entropy during rearrangements. Accordingly, what can be considered the next-order approximation is the SMOG class of structure-based models. With these models, we construct force fields that incorporate known basins of attraction, allowing us to systematically include additional non-specific contributions. This type of approach not only provides a structural/energetic framework for understanding biological processes, but it can be used to pinpoint the precise functional role of any number of molecular forces that are present in the cell.

One area of interest in our group is understanding how steric interactions can shape the free-energy landscapes of large assemblies. In this area, structure-based models are indispensable tools for characterizing the dynamics. In many cases, we have found that the shape of the ribosome limits the dynamics to such a large extent that only a few possible pathways may connect distinct conformational states. Further, these sterics-only models often predict free-energy barriers that are consistent with experimentally-measured timescales. For some specific examples, see:

M. Levi, K. Walak, A. Wang, U. Mohanty, P.C. Whitford. A steric gate controls P/E hybrid-state formation of tRNA on the ribosome. Nature Communications 11, 5706, 2020.

H. Yang, J. Perrier, P. C. Whitford. Disorder guides domain rearrangement in EF-Tu. Proteins: Structure, Function, Bioinformatics 86, 1037-1046, 2018.

H. Yang, J. K. Noel, P.C. Whitford. Anisotropic fluctuations in the ribosome determine tRNA kinetics. J. Phys. Chem. B. 121, 10593-10601, 2017.

J. K. Noel, P. C. Whitford. How EF-Tu can contribute to efficient proofreading of aa-tRNA by the ribosome. Nature Communications 7, 13314, 2016.

K. Nguyen, P. C. Whitford. Steric interactions lead to collective head tilting during mRNA-tRNA translocation on the ribosome. Nature Communications 7, 10586, 2016.

J. K. Noel, J. Chahine, V. B. P. Leite, P. C. Whitford. Capturing transition paths and transition states for conformational rearrangements in the ribosome. Biophys. J. 107, 2872-2881, 2014.

Another area of interest in our group is the identification and characterization of order-disorder transitions during functional dynamics. Many examples can be found in the literature, including: localized unfolding (also known as "cracking") that can dictate the free-energy barrier heights, global unfolding that can enable complete rearrangements of interfaces, or changes in configurational entropy that guide large assemblies during functional cycles. In a recent study, we even found that steric interactions and disorder can guide the maturation process of a complete viral capsid.

P. C. Whitford, W. Jiang, P. Serwer. Simulations of phase T7 capsid expansion reveal the role of molecular steric on dynamics. Viruses 12, 1273, 2020.

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