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On the improvement of free-energy calculation from steered molecular dynamics simulations using adaptive stochastic perturbation protocols.

ABSTRACT: The potential of mean force (PMF) calculation in single molecule manipulation experiments performed via the steered molecular dynamics (SMD) technique is a computationally very demanding task because the analyzed system has to be perturbed very slowly to be kept close to equilibrium. Faster perturbations, far from equilibrium, increase dissipation and move the average work away from the underlying free energy profile, and thus introduce a bias into the PMF estimate. The Jarzynski equality offers a way to overcome the bias problem by being able to produce an exact estimate of the free energy difference, regardless of the perturbation regime. However, with a limited number of samples and high dissipation the Jarzynski equality also introduces a bias. In our previous work, based on the Brownian motion formalism, we introduced three stochastic perturbation protocols aimed at improving the PMF calculation with the Jarzynski equality in single molecule manipulation experiments and analogous computer simulations. This paper describes the PMF reconstruction results based on full-atom molecular dynamics simulations, obtained with those three protocols. We also want to show that the protocols are applicable with the second-order cumulant expansion formula. Our protocols offer a very noticeable improvement over the simple constant velocity pulling. They are able to produce an acceptable estimate of PMF with a significantly reduced bias, even with very fast perturbation regimes. Therefore, the protocols can be adopted as practical and efficient tools for the analysis of mechanical properties of biological molecules.

SUBMITTER: Perisic O

PROVIDER: S-EPMC4169427 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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On the improvement of free-energy calculation from steered molecular dynamics simulations using adaptive stochastic perturbation protocols.

Perišić Ognjen O Lu Hui H

PloS one 20140918 9

The potential of mean force (PMF) calculation in single molecule manipulation experiments performed via the steered molecular dynamics (SMD) technique is a computationally very demanding task because the analyzed system has to be perturbed very slowly to be kept close to equilibrium. Faster perturbations, far from equilibrium, increase dissipation and move the average work away from the underlying free energy profile, and thus introduce a bias into the PMF estimate. The Jarzynski equality offers ...[more]

PMID: 25232859

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Project description:NMR spectroscopic analysis of the C-terminal Kunitz domain fragment (alpha3(VI)) from the human alpha3-chain of type VI collagen has revealed that the side chain of Trp21 exists in two unequally populated conformations. The major conformation (M) is identical to the conformation observed in the X-ray crystallographic structure, while the minor conformation (m) cannot structurally be resolved in detail by NMR due to insufficient NOE data. In the present study, we have applied: (1) rigid and adiabatic mapping, (2) free energy simulations, and (3) molecular dynamic simulations to elucidate the structure of the m conformer and to provide a possible pathway of the Trp21 side chain between the two conformers. Adiabatic energy mapping of conformations of the Trp21 side chain obtained by energy minimization identified two energy minima: One corresponding to the conformation of Trp21 observed in the X-ray crystallographic structure and solution structure of alpha3(VI) (the M conformation) and the second corresponding to the m conformation predicted by NMR spectroscopy. A transition pathway between the M and m conformation is suggested. The free-energy difference between the two conformers obtained by the thermodynamic integration method is calculated to 1.77+/-0.7 kcal/mol in favor of the M form, which is in good agreement with NMR results. Structural and dynamic properties of the major and minor conformers of the alpha3(VI) molecule were investigated by molecular dynamic. Essential dynamics analysis of the two resulting 800 ps trajectories reveals that when going from the M to the m conformation only small, localized changes in the protein structure are induced. However, notable differences are observed in the mobility of the binding loop (residues Thr13-Ile18), which is more flexible in the m conformation than in the M conformation. This suggests that the reorientation of Trp2 might influence the inhibitory activity against trypsin, despite the relative large distance between the binding loop and Trp21.

Dataset Information

On the improvement of free-energy calculation from steered molecular dynamics simulations using adaptive stochastic perturbation protocols.

Publications

On the improvement of free-energy calculation from steered molecular dynamics simulations using adaptive stochastic perturbation protocols.

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