Paul C Whitford

Associate Professor

Department of Physics
Northeastern University
123 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
Director's Postdoctoral Fellow, 2009-2012, Los Alamos National Laboratory
Senior Scientist, 2012 Rice University
Assistant Professor, 2012-2018 Northeastern University

Associate Professor, 2018-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, this leads to the well-known harmonic oscillator description being adopted, where a particular energetic basin is described as a quadratic function in a given coordinate space. For biomolecular dynamics, the lowest-order description is often provided by 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 forcefields that incorporate known basins of attraction, which allows 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 allows us to pinpoint the precise functional role of any number of molecular forces that are present in the cell.

Of particular 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. For a detailed look at order-disorder transitions in molecular biology, we refer you to our recent review article on the topic.

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