College of Liberal Arts & Sciences

Multiple pathways of helix folding from kinetic coarse grained models

Tuesday, September 10, 2019

Title:            Multiple pathways of helix folding from kinetic coarse grained models
Time:           11:00 a.m.
Location:    Room 202 MRB
Presenter:   Krzysztof Kuczera (Professor, Department of Chemistry, The University of Kansas, Lawrence, KS)

Nanosecond laser temperature jump spectroscopy and molecular dynamics (MD) simulations were used to study the helix-coil transition in a 21-residue helix-forming peptide. Two relaxation times were detected a low pH, at which the single histidine in the peptide sequence is protonated. A slower component of 300-400 ns was assigned to helix-coil relaxation. A faster component of 20-35 ns was also characterized, indicating a complex path of peptide kinetics.

MD simulations were carried out to model the mechanism of formation of the peptide alpha-helical structure. A 12 microsecond MD trajectory in explicit solvent yielded structural and dynamic properties in good agreement with experimental data. Clustering and optimal dimensionality reduction were applied to produce low-dimensional coarse-grained models of the underlying kinetic network in terms of 2-5 metastable states. The high-entropy “coil” metastable set contains the largest number of structures, but the helix state was also structurally heterogeneous. The intermediate states contain the fewest structures, have lowest populations and the shortest lifetimes. As the number of considered metastable states increases, more intermediates and more folding paths appear in the coarse- grained models. One of these intermediates corresponds to the transition state for folding, which involves an “off-center” helical region over residues 11-16. The simulation data further suggest that the fast kinetic time scale should be assigned to correlated breaking/formation of blocks of several adjacent helical hydrogen bonds.

The same computational analysis was also applied to a 13-microsecond MD trajectory of the peptide with the neutral form of its histidine residue, corresponding to a higher pH. The loss of the histidine proton induces significant changes in the free energy landscape. This form has a higher helix content than the protonated peptide, in accord with experimental observations. Additionally, the kinetic network and folding pathway are markedly different.

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