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Mechanisms of helical peptide folding

Monday, April 18, 2PM – 3PM
ACE 6.304

Krzysztof Kuczera

The fold of proteins into native three-dimensional structures is a pre-requisite for correct biological function. Formation of elementary building blocks â€“ alpha-helices and beta-sheets lies at the heart of protein folding. Progress in computer power and algorithms allows us to realistically simulate the folding equilibrium and kinetics for peptide systems of moderate size, which occur on time scales of 10-100 ns. We report the results of direct all-atom molecular dynamics simulations for a series of helix-forming peptides ranging in size from 5 to 21 residues1. Using several popular molecular mechanics force fields, we obtain structures and folding rates in good quantitative agreement with available experimental data. Our simulations also provide microscopically detailed information about sampled structures and folding pathways that is not easily accessible by experimental measurement. Interestingly, the details of the folding pathways exhibit some variation with peptide size and force field employed. Thus, accuracy of potential energy parameters, rather than conformational sampling, may be the limiting factor in current molecular simulations. Also, new and more detailed experimental data are needed to further improve models for the elementary processes of secondary structure formation.

References: 1. W. Hegefeld, S.-E. Chen, K. DeLeon, K. Kuczera and G.S. Jas. (2010) Helix formation in a pentapeptide: Experiment and force-field dependent dynamics. J.Phys.Chem.B, 114:12391-12402.

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