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Mechanical unfolding of a beta-hairpin using molecular dynamics.

ABSTRACT: Single-molecule mechanical unfolding experiments have the potential to provide insights into the details of protein folding pathways. To investigate the relationship between force-extension unfolding curves and microscopic events, we performed molecular dynamics simulations of the mechanical unfolding of the C-terminal hairpin of protein G. We have studied the dependence of the unfolding pathway on pulling speed, cantilever stiffness, and attachment points. Under conditions that generate low forces, the unfolding trajectory mimics the untethered, thermally accessible pathway previously proposed based on high-temperature studies. In this stepwise pathway, complete breakdown of backbone hydrogen bonds precedes dissociation of the hydrophobic cluster. Under more extreme conditions, the cluster and hydrogen bonds break simultaneously. Transitions between folding intermediates can be identified in our simulations as features of the calculated force-extension curves.

SUBMITTER: Bryant Z

PROVIDER: S-EPMC1300663 | biostudies-other | 2000 Feb

REPOSITORIES: biostudies-other

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Mechanical unfolding of a beta-hairpin using molecular dynamics.

Bryant Z Z Pande V S VS Rokhsar D S DS

Biophysical journal 20000201 2

Single-molecule mechanical unfolding experiments have the potential to provide insights into the details of protein folding pathways. To investigate the relationship between force-extension unfolding curves and microscopic events, we performed molecular dynamics simulations of the mechanical unfolding of the C-terminal hairpin of protein G. We have studied the dependence of the unfolding pathway on pulling speed, cantilever stiffness, and attachment points. Under conditions that generate low for ...[more]

PMID: 10653773

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Project description:The conformations and stabilities of the β-hairpin model peptides of Waters (Riemen, A. J.; Waters, M. L. Biochemistry 2009, 48, 1525; Hughes, R. M.; Benshoff, M. L.; Waters, M. L. Chemistry 2007, 13, 5753) have been experimentally characterized as a function of lysine ε-methylation. These models were developed to explore molecular recognition of known epigenetic recognition motifs. This system offered an opportunity to computationally examine the role of cation-π interactions, desolvation of the ε-methylated ammonium groups, and aromatic/aromatic interactions on the observed differences in NMR spectra. AMOEBA, a second-generation force field (Ponder, J. W.; Wu, C.; Ren, P.; Pande, V. S.; Chodera, J. D.; Schnieders, M. J.; Haque, I.; Mobley, D. L.; Lambrecht, D. S.; DiStasio, R. A., Jr.; Head-Gordon, M.; Clark, G. N.; Johnson, M. E.; Head-Gordon, T. J. Phys. Chem. B 2010, 114, 2549), was chosen as it includes both multipole electrostatics and polarizability thought to be essential to accurately characterize such interactions. Independent parametrization of ε-methylated amines was required from which aqueous solvation free energies were estimated and shown to agree with literature values. Molecular dynamics simulations (100 ns) using the derived parameters with model peptides, such as Ac-R-W-V-W-V-N-G-Orn-K(Me)(n)-I-L-Q-NH(2), where n = 0, 1, 2, or 3, were conducted in explicit solvent. Distances between the centers of the indole rings of the two-tryptophan residues, 2 and 4, and the ε-methylated ammonium group on Lys-9 as well as the distance between the N- and C-termini were monitored to estimate the strength and orientation of the cation-π and aromatic/aromatic interactions. In agreement with the experimental data, the stability of the β-hairpin increased significantly with lysine ε-methylation. The ability of MD simulations to reproduce the observed NOEs for the four peptides was further estimated for the monopole-based force fields, AMBER, CHARMM, and OPLSAA. AMOEBA correctly predicted over 80% of the observed NOEs for all 4 peptides, while the three-monopole force fields were 40-50% predictive in only 2 cases and approximately 10% in the other 10 examples. Preliminary analysis suggests that the decreased cost of desolvation of the substituted ammonium group significantly compensated for the reduced cation-π interaction resulting from the increased separation due to steric bulk of the ε-methylated amines.

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Mechanical unfolding of a beta-hairpin using molecular dynamics.

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Mechanical unfolding of a beta-hairpin using molecular dynamics.

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