Cameron F. Abrams
Assistant Professor
Department of Chemical and Biological Engineering
Drexel University

Molecular Simulation Studies of Chaperonin Structure and Function

Chaperonins are a class of protein complexes responsible for enhancing both the efficiency and rate of protein folding in vivo, and are sometimes described as “protein folding catalysts.”  The prototypical E. coli chaperonin GroEL is the most-studied member of its class, and yet its mechanism of action is poorly understood.  Roughly speaking, GroEL tetradecamers bind and encapsulate newly translated polypeptides, blocking pathways that lead to pre-folding aggregation.  Through a complicated and still hypothetical mechanism, GroEL then transfers the energy of nucleotide binding and hydrolysis to the substrate polypeptide to help it both reach a folded state at an accelerated rate and to dislodge it from GroEL.  In this presentation, I will discuss two major aspects of the structure-function relationship of GroEL:  (1) the effect of passive confinement of a polypeptide on its folding/unfolding equilibrium, and (2) the detailed role of nucleotide binding on driving conformational changes in GroEL itself that lend it active functionality in binding and releasing substrate polypeptides.  In the first instance, we have performed novel density-of-states Monte Carlo simulations of model polypeptides in passive spherical cavities.  These simulations are unique in that they reveal the complete thermodynamics of the folding/unfolding equilibrium for the model peptide, allowing us to propose a more robust model for how the phase transition temperature scales with cavity size.  In the second instance, we have performed large-scale molecular dynamics simulations of an isolated GroEL subunit (~570 kDa) in explicit water both with and without weakly bound adenosine triphosphate nucleotide (ATP), with the objective of observing the so-called t to r transition in which the subunit transitions from a low-affinity to a high-affinity state for nucleotide.  Finally, I discuss some recent results from molecular-dynamics simulations of GroEL heptamers aimed at detailed understanding of cooperative structural transitions in the GroEL functional pathway.

Please join us for refreshments at 10:45 a.m.