Calculating free-energy profiles in biomolecular systems from fast nonequilibrium processes

Forney, Michael W.; Janosi, Lorant; Kosztin, Ioan

doi:10.1103/physreve.78.051913

Cited by 32 publications

(43 citation statements)

References 37 publications

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“…The premises for such investigations are the high-resolution atomic structure of the channels and accurate force fields to describe molecular interactions at atomic level. Extensive efforts to obtain better atomistic MD force fields in general [1], [2], and for ionic interactions in particular [3] have overcome many former protein channel modeling challenges, like the strong polarization effects on the environment [4], [5]. The considerably larger simulation timescales attainable nowadays enhanced our understanding of transporters, known gated systems, such as the voltage- or ligand-gated channels [6], but also lead to new findings, such as the presence of gating mechanisms in some of the aquaporin channels as well [7].…”

Section: Introductionmentioning

confidence: 99%

The Gating Mechanism of the Human Aquaporin 5 Revealed by Molecular Dynamics Simulations

Janosi

Ceccarelli

2013

PLoS ONE

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Aquaporins are protein channels located across the cell membrane with the role of conducting water or other small sugar alcohol molecules (aquaglyceroporins). The high-resolution X-ray structure of the human aquaporin 5 (HsAQP5) shows that HsAQP5, as all the other known aquaporins, exhibits tetrameric structure. By means of molecular dynamics simulations we analyzed the role of spontaneous fluctuations on the structural behavior of the human AQP5. We found that different conformations within the tetramer lead to a distribution of monomeric channel structures, which can be characterized as open or closed. The switch between the two states of a channel is a tap-like mechanism at the cytoplasmic end which regulates the water passage through the pore. The channel is closed by a translation of the His67 residue inside the pore. Moreover, water permeation rate calculations revealed that the selectivity filter, located at the other end of the channel, regulates the flow rate of water molecules when the channel is open, by locally modifying the orientation of His173. Furthermore, the calculated permeation rates of a fully open channel are in good agreement with the reported experimental value.

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Section: Introductionmentioning

confidence: 99%

The Gating Mechanism of the Human Aquaporin 5 Revealed by Molecular Dynamics Simulations

Janosi

Ceccarelli

2013

PLoS ONE

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“…13,14 Although under near-equilibrium conditions JE has been verified in RNA stretching experiments, 15,16 calculations from far-from-equilibrium trajectories require ex-haustive sampling. A recently developed generalization, based on Crooks' transient fluctuation theorem 17 allows the calculation of ⌬F from fewer fast SMD pulls 18,19 performed in both forward and time reversed directions. Nevertheless, accurate PMF calculations in complex systems remain a formidable task especially when numerous microscopic degrees of freedom that decorrelate over long characteristic times contribute to the accuracy of the free energy profile.…”

Section: Introductionmentioning

confidence: 99%

Accelerating flat-histogram methods for potential of mean force calculations

Janosi

Doxastakis

2009

The Journal of Chemical Physics

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Potential of mean force calculations along a reaction coordinate (RC) demand exhaustive sampling, which often leads to prohibitively long computational times. The expanded ensemble density of states (EXEDOS) [E. B. Kim, R. Faller, Q. Yan et al., J. Chem. Phys. 117, 7781 (2002)] is a simple flat-histogram Monte Carlo method based on the density of states algorithm proposed by Wang and Landau [Phys. Rev. Lett. 86, 2050 (2001)]. EXEDOS offers the advantage of continuous uniform sampling of the RC with no a priori knowledge of the free energy profile. However, the method is not certain to converge within accessible simulation time. Furthermore, the strongly asymmetric distribution of tunneling times inherent in flat-histogram sampling imposes additional limitations. We propose several improvements that accelerate the EXEDOS method and can be generally applicable in free energy calculations. First, we propose an asynchronous parallel implementation of the density of states algorithm in a multiple-walkers multiple-windows scheme and extend the algorithm in an expanded ensemble [(MW)(2)-XDOS] for PMF calculations as the original EXEDOS. Despite the nonideal scaling over a number of processors this technique overcomes limitations by extreme values of tunneling times and allows consistent evaluations of performance. The second set of improvements addresses the dependence of convergence times on system size, density, and sampling rate of the RC. At low densities, the coupling of (MW)(2)-XDOS with the rejection-free geometric cluster move provides impressive performance that overshadows any other technique. However, the limited applicability of cluster moves at high densities requires an alternative approach. We propose the coupling of (MW)(2)-XDOS with preferential sampling methods. In the systems studied, single displacements in the proximity of particles defining the RC accelerate calculations significantly and render the simulation nearly size-independent. A further modification of preferential sampling involves collective displacements of particles performed in a "smart Monte Carlo" scheme. This "local Brownian dynamics" algorithm can be generally applicable to many free energy simulation methods and would be particularly beneficial at high densities and molecular systems with strong intramolecular potentials.

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“…In particular, we demonstrate the application and interpretation of PCA of nonequilibrium data. Adopting decaalanine in vacuo as a well-established model problem to test TMD, 35,[38][39][40][41] we compare and analyze unbiased MD and TMD data.…”

Section: ∆G(s) =mentioning

confidence: 99%

Principal component analysis of nonequilibrium molecular dynamics simulations

Post

Wolf

Stock

2019

The Journal of Chemical Physics

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Principal component analysis (PCA) represents a standard approach to identify collective variables {x i } = x, which can be used to construct the free energy landscape ∆G(x) of a molecular system. While PCA is routinely applied to equilibrium molecular dynamics (MD) simulations, it is less obvious how to extend the approach to nonequilibrium simulation techniques. This includes, e.g., the definition of the statistical averages employed in PCA, as well as the relation between the equilibrium free energy landscape ∆G(x) and energy landscapes ∆G(x) obtained from nonequilibrium MD. As an example for a nonequilibrium method, "targeted MD" is considered which employs a moving distance constraint to enforce rare transitions along some biasing coordinate s. The introduced bias can be described by a weighting function P (s), which provides a direct relation between equilibrium and nonequilibrium data, and thus establishes a well-defined way to perform PCA on nonequilibrium data. While the resulting distribution P(x) and energy ∆G ∝ ln P will not reflect the equilibrium state of the system, the nonequilibrium energy landscape ∆G(x) may directly reveal the molecular reaction mechanism. Applied to targeted MD simulations of the unfolding of decaalanine, for example, a PCA performed on backbone dihedral angles is shown to discriminate several unfolding pathways. Although the formulation is in principle exact, its practical use depends critically on the choice of the biasing coordinate s, which should account for a naturally occurring motion between two well-defined end-states of the system.

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Calculating free-energy profiles in biomolecular systems from fast nonequilibrium processes

Cited by 32 publications

References 37 publications

The Gating Mechanism of the Human Aquaporin 5 Revealed by Molecular Dynamics Simulations

The Gating Mechanism of the Human Aquaporin 5 Revealed by Molecular Dynamics Simulations

Accelerating flat-histogram methods for potential of mean force calculations

Principal component analysis of nonequilibrium molecular dynamics simulations

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