Multidimensional free‐energy calculations using the weighted histogram analysis method

Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal; Swendsen, Robert H.; Kollman, Peter A.

doi:10.1002/jcc.540161104

Cited by 789 publications

(787 citation statements)

References 18 publications

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“…In the present study, r_ cut is set as 1. [53][54][55] is used for data analysis by combining the data at all temperatures. The Rg, fraction of native contacts (Q), specific heat capacity (C v /k B ), and potential energy from direct simulations as well as WHAM are shown in Figure 2.…”

Section: Resultsmentioning

confidence: 99%

Is there an en route folding intermediate for cold shock proteins?

Huang

Shakhnovich

2012

Protein Science

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Cold shock proteins (Csps) play an important role in cold shock response of a diverse number of organisms ranging from bacteria to humans. Numerous studies of the Csp from various species showed that a two-state folding mechanism is conserved and the transition state (TS) appears to be very compact. However, the atomic details of the folding mechanism of Csp remain unclear. This study presents the folding mechanism of Csp in atomic detail using an all-atom Go model-based simulations. Our simulations predict that there may exist an en route intermediate, in which b strands 1-2-3 are well ordered and the contacts between b1 and b4 are almost developed. Such an intermediate might be too unstable to be detected in the previous fluorescence energy transfer experiments. The transition state ensemble has been determined from the P fold analysis and the TS appears even more compact than the intermediate state.

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Section: Resultsmentioning

confidence: 99%

Is there an en route folding intermediate for cold shock proteins?

Huang

Shakhnovich

2012

Protein Science

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“…Future work will address the estimation of the relative free energy of the different minima sampled in this study, using the configurational entropy derived from the harmonic or quasiharmonic partition functions (McQuarrie, 1973;Levy et al, 1984). The weighted histogram analysis method (Kumar et al, 1992) can also be used to combine trajectory data to yield the free energies and, thus, the relative probabilities of different conformational states (Boczko & Brooks, 1995;Kumar et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Locally accessible conformations of proteins: Multiple molecular dynamics simulations of crambin

1998

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Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vicinity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution generated by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal components analysis (PCA). Four different major conformational regions are found. In general, a trajectory samples only one region and few transitions between the regions are observed. Consequently, the averages of structural and dynamic properties over the ten trajectories differ significantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the utilization of MD simulations for a wide range of problems, such as comparisons with X-ray or NMR data. The overall average structure is significantly closer to the X-ray structure than any of the individual trajectory average structures. The high frequency (less than 10 ps) atomic fluctuations from the ten trajectories tend to be similar, but the lower frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory.

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“…72,73 After the simulations, the effect of the restraints on the final results can be removed with a variety of methods. 73,74 Trzesniak et al 72 provides a recent, comparative review of the methods to compute PMFs.…”

Section: Computational Methods and Detailsmentioning

confidence: 99%

Metal Cation Complexation with Natural Organic Matter in Aqueous Solutions: Molecular Dynamics Simulations and Potentials of Mean Force

Iskrenova-Tchoukova¹,

Kalinichev²,

2010

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Natural organic matter (NOM, or humic substance) has a known tendency to form colloidal aggregates in aqueous environments, with the composition and concentration of cationic species in solution, pH, temperature, and the composition of the NOM itself playing important roles. Strong interaction of carboxylic groups of NOM with dissolved metal cations is thought to be the leading chemical interaction in NOM supramolecular aggregation.Computational molecular dynamics (MD) study of the interactions of Na + , Mg 2+ , and Ca 2+ with the carboxylic groups of a model NOM fragment and acetate anions in aqueous solutions provides new quantitative insight into the structure, energetics, and dynamics of the interactions of carboxylic groups with metal cations, their association and the effects of cations on the colloidal aggregation of NOM molecules. Potentials of mean force and the equilibrium constants describing overall ion association and the distribution of metal cations between contact ion pairs and solvent separated ions pairs were computed from free MD simulations and restrained umbrella sampling calculations. The results provide insight into the local structural environments of metal-carboxylate association and the dynamics of exchange among these sites. All three cations prefer contact ion pair to solvent separated ion pair coordination, and Na + and Ca 2+ show a strong preference for bidentate contact ion pair formation. The average residence time of a Ca 2+ ion in a contact ion pair with the carboxylic groups is of the order of 0.5 ns, whereas the corresponding residence time of a Na + ion is only between 0.02 and 0.05 ns. The average residence times of a Ca 2+ ion in a bidentate coordinated contact ion pair vs. a monodentate coordinated contact ion pair are about 0.5 ns and about 0.08 ns, respectively. On the 10-ns time scale of our simulations, aggregation of the NOM molecules occurs in the presence of Ca 2+ but not Na + or Mg 2+ . These results agree with previous experimental observations and are explained 3 by both Ca 2+ ion-bridging between NOM molecules and decreased repulsion between the NOM molecules due to the reduced net charge of the NOM-metal complexes. Simulations on a larger scale are needed to further explore the relative importance of the different aggregation mechanisms and the stability of NOM aggregates.4

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Multidimensional free‐energy calculations using the weighted histogram analysis method

Cited by 789 publications

References 18 publications

Is there an en route folding intermediate for cold shock proteins?

Is there an en route folding intermediate for cold shock proteins?

Locally accessible conformations of proteins: Multiple molecular dynamics simulations of crambin

Metal Cation Complexation with Natural Organic Matter in Aqueous Solutions: Molecular Dynamics Simulations and Potentials of Mean Force

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