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Helix formation in a pentapeptide: Experiment and force-field dependent dynamics.

W. Hegefeld, S.-E. Chen, K. DeLeon, K. Kuczera and G.S. Jas.

J. Phys. Chem. B, 114:12391-12402 (2010).

We used a combined approach of experiment and simulation to determine the helical population and folding pathway of a small helix forming blocked pentapeptide, Ac-(Ala)5-NH2. Experimental structural characterization of this blocked peptide was carried out with far UV circular dichroism spectroscopy, FTIR and NMR measurements. These measurements confirm the presence of the α−helical state in buffer solution. Direct molecular dynamics and replica-exchange simulations of the pentapeptide were performed using several popular force fields with explicit solvent. The simulations yielded statistically reliable estimates of helix populations, melting curves, folding and nucleation times. The distributions of conformer populations are used to measure folding cooperativity. Finally, a statistical analysis of the sample of helix-coil transition paths was performed. The details of the calculated helix populations, folding kinetics and pathways vary with the employed force field. Interestingly, the helix populations, folding and unfolding times obtained from most of the studied force fields are in qualitative agreement with each other and with available experimental data, with the deviations corresponding to several kcal/mol in energy at 300 K. Most of the force fields also predict qualitatively similar transition paths, with unfolding initiated at the C-terminus. Accuracy of potential energy parameters, rather than conformational sampling may be the limiting factor in current molecular simulations.

Blocked Ala5 structure with H-honds. Phi-psi map of sampled conformations in 1 microsecond MD with OPLS-AA/TIP3.

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Reorientations of Aromatic Acids and Their Side Chains Models: Anisotropy Measurements and Molecular Dynamics Simulations.

K. Kuczera, J. Unruh, C.K. Johnson and G.S. Jas.

J.Phys.Chem. A, 114:133-142 (2010).

We present a study of reorientation dynamics of the three aromatic amino acids and their side chain models in aqueous solution. Experimentally, anisotropy decay measurements with picosecond time resolution were performed for blocked tryptophan, tyrosine and phenyalanine and model compounds p-cresol and 3-methylindole. Computationally, rotational diffusion was modeled by molecular dynamics simulations for the three aromatic residues and their side chain models: benzene, toluene, phenol, p-cresol, indole and 3-methylindole in explicit water. Our simulations used the CHARMM protein force field and associated TIP3P water model and tend to overestimate the rotational correlation times. However, the simulations yield several interesting qualitative insights into reorientational motions that complement the experimental measurements. The effects of substituent and temperature on reorientations of the parent compounds are well reproduced computationally. Additionally, simulations indicate strongly anisotropic reorientations for most of the studied compounds and a separation of time scales between conformational dynamics and rotational diffusion. Comparison with continuum hydrodynamic models suggests that we may consider that the blocked amino acids move under stick boundary conditions, while dynamics for most of the model compounds falls between stick and slip conditions. Our systematic treatment of blocked amino acids, starting from the parent compounds - benzene, phenol and indole, provides a baseline for understanding the anisotropy decay signals of more complicated peptide systems.

Structures of sidechains and models. Simulated correlation functions for Trp model reorientations.

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