Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling

Torrie, G. M.; Valleau, J. P.

doi:10.1016/0021-9991(77)90121-8

Cited by 5,485 publications

(5,096 citation statements)

References 17 publications

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“…40 For the 1D projection, the reaction coordinate was the displacement of the center-of-mass of the unsaturated tail of a selected lipid molecule from the center of the water layer normal to the bilayer. The value Figure 10.…”

Section: Methodsmentioning

confidence: 99%

Solvent-Exposed Tails as Prestalk Transition States for Membrane Fusion at Low Hydration

et al. 2010

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Membrane fusion is a key step in intracellular trafficking and viral infection. The underlying molecular mechanism is poorly understood. We have used molecular dynamics simulations in conjunction with a coarse grained model to study early metastable and transition states during the fusion of two planar palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayers separated by five waters per lipid in the cis leaflets at zero tension. This system mimics the contact area between two vesicles with large diameters compared to the membrane thickness at conditions where fusion may start in the core of the contact area. At elevated temperatures, the two proximal leaflets become connected via multiple lipid molecules and form a stalklike structure. At room temperature, this structure has a free energy of 3k B T and is separated from the unconnected state by a significant free energy barrier of 20k B T. Stalk formation is initiated by the establishment of a localized hydrophobic contact between the bilayers. This contact is either formed by two partially splayed lipids or a single fully splayed one leading to the formation of a (metastable) splayed lipid bond intermediate. These findings indicate that, for low hydration, early membrane fusion kinetics is not determined by the stalk energy but by the energy of prestalk transition states involving solvent-exposed lipid tails.

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Section: Methodsmentioning

confidence: 99%

Solvent-Exposed Tails as Prestalk Transition States for Membrane Fusion at Low Hydration

et al. 2010

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“…The selected distances depend on the reaction and the step studied (see below). The umbrella sampling approach 46 was used to constraint the system close to a particular value of the RC by means of the addition of a harmonic potential with a force constant of 2500 kJ·mol -1 ·Å -2 , which allowed good overlap between consecutive simulation windows.…”

Section: Free Energy Calculationsmentioning

confidence: 99%

Enzyme Promiscuity in Enolase Superfamily. Theoretical Study of o-Succinylbenzoate Synthase Using QM/MM Methods

et al. 2015

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The promiscuous activity of the enzyme o-Succinylbenzoate Synthase (OSBS) from the actinobacteria Amycolatopsis is investigated by means of QM/MM methods, using both Density Functional Theory and Semiempirical Hamiltonians. This enzyme catalyzes not only the dehydration of 2-succinyl-6R-hydroxy-2,4-cyclohexadiene-1R-carboxylate but also catalyzes racemization of different acylaminoacids, being N-succinyl-Rphenylglycine the best substrate. We investigated the molecular mechanisms for both reactions exploring the Potential Energy Surface. Then, Molecular Dynamics simulations were performed to obtain the free energy profiles and the averaged interaction energies of enzymatic residues with the reacting system. Our results confirm the plausibility of the reaction mechanisms proposed in the literature, with a good agreement between theoretical and experimentally-derived activation free energies. Our simulations unravel the role played by the different residues in each of the two possible reactions. The presence of flexible loops in the active site and the selection of structural modifications in the substrate seem to be key elements to promote the promiscuity of this enzyme.

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“…For the studied association reaction L + P ⇌ LP between protein P and ligand L the potential of mean force as assessed by the umbrella sampling simulations [25] reflects the ratio of bound and unbound states as:…”

Section: Binding Free Energymentioning

confidence: 99%

“…We focused our efforts on evaluating the PMF for the two binding sites described earlier. We used the umbrella sampling method [25] to compute the PMF, where an artificial biasing potential is added to glutamate to force it to sample the regions of interest, from the binding site in the receptor to bulk solution. For convenience, the origin of the coordinate system was placed at the position of the glutamate after 100 ns of simulation, with the z-axis along the path away from the binding site.…”

Section: Binding Free Energymentioning

confidence: 99%

Binding of glutamate to the umami receptor

Cascales

Costa

Groot

et al. 2010

Biophysical Chemistry

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The umami taste receptor is a heterodimer composed of two members of the T1R taste receptor family: T1R1 and T1R3. It detects glutamate in humans, and is a more general amino acid detector in other species. We have constructed homology models of the ligand binding domains of the human umami receptor (based on crystallographic structures of the metabotropic glutamate receptor of the central nervous system). We have carried out molecular dynamics simulations of the ligand binding domains, and we find that the likely conformation is that T1R1 receptor protein exists in the closed conformation, and T1R3 receptor in the open conformation in the heterodimer. Further, we have identified the important binding interactions and have made an estimate of the relative free energies associated with the two glutamate binding sites.

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Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling

Cited by 5,485 publications

References 17 publications

Solvent-Exposed Tails as Prestalk Transition States for Membrane Fusion at Low Hydration

Solvent-Exposed Tails as Prestalk Transition States for Membrane Fusion at Low Hydration

Enzyme Promiscuity in Enolase Superfamily. Theoretical Study of o-Succinylbenzoate Synthase Using QM/MM Methods

Binding of glutamate to the umami receptor

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