Extensive all-atom Monte Carlo sampling and QM/MM corrections in the SAMPL4 hydration free energy challenge

Genheden, Samuel; Martínez, Ana; Criddle, Michael P.; Essex, Jonathan W.

doi:10.1007/s10822-014-9717-3

Cited by 52 publications

(82 citation statements)

References 38 publications

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“…In all cases, the molecules are simulated in a classical fixed-charge potential and the system is reweighted to a QM/MM Hamiltonian. A previous study using NBB showed that the QM/MM Hamiltonian provides a small but statistically significant improvement over standard MM force fields at matching experimental data [249,257,296]. We evaluate whether the magnitude of this benefit changes when different methods are used to reweight the same MM configurations to the same QM/MM Hamiltonian.…”

Section: Conclusion and Future Outlookmentioning

confidence: 98%

“…The simplest method to obtain free energy differences via Hamiltonian reweighting involves reweighting from one sampled to one unsampled state, generally referred to as exponential reweighting or the Zwanzig equation [191,238,240,[242][243][244][247][248][249][250]252], which is simply eq 6.1. This method produces asymptotically unbiased free energy differences in the limit of large sampling.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

“…Warshel et al [238] introduced a method based on the pioneering work of Kirkwood [239] and Zwanzig [191] to calculate free energies in complex Hamiltonians indirectly by simulating in a cheap potential and calculating ensemble averages in the expensive potential using Boltzmann reweighting, thus avoiding direct simulation in the expensive potential [240][241][242][243][244][245][246][247][248][249][250][251][252][253][254][255][256][257][258]. The formula for estimating the ensemble average in a target state given samples in another state is [191]:…”

Section: Introductionmentioning

confidence: 99%

“…In previous studies employing Boltzmann reweighting, poor overlap was attributed to differences in the intramolecular interactions between the cheap and expensive potential [247,253]. This poor overlap has led researchers to using alternate reweighting strategies such as replacing the total energy difference in equation 4.1 with just the difference in intermolecular interactions, while holding the intramolecular interactions constant [247][248][249][250]. The target potential with this approach has intermolecular interactions that correspond with the expensive potential and intramolecular interactions at the cheaper level of theory.…”

Section: Introductionmentioning

confidence: 99%

“…The additional free energy cost to convert the intramolecular interactions from the cheap to expensive Hamiltonian is assumed to be negligible. The bias introduced by this approximation is in many cases small, [247,249,250] but there is presently no rigorous bounds or systematic prediction of the error introduced by this approximation. Therefore we will not investigate this approach here.…”

Section: Introductionmentioning

confidence: 99%

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Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Dybeck

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AcknowledgementsI would like to acknowledge the guidance and support provided by my advisor MichaelShirts. I would also like to thank Levi Naden, Natalie Schieber, Nate Abraham and the entire Shirts group for their help and technical support during my research. I also would like to acknowledge the UVA high performance computing team for the computational resources necessary to complete this work. Finally, I would like to acknowledge the endless love and support that my friends and family provided me during this challenging Ph.D. journey.iii AbstractThe presence of multiple stable crystal structures in solid organic materials can limit their commercial viability when two or more observable polymorphs exhibit markedly different physical properties. Unintended restructuring events have hindered pharmaceutical solid form development in numerous therapeutic candidates and have led to costly market recalls.Conversely, intentional synthesis of a metastable form has led to significantly more favorable performance in numerous materials.Current computational methods for predicting polymorphic behavior evaluate candidate crystal structures based on the minimized lattice energy. However, these static lattice energybased approaches generate far more lattice energy minima than there are experimentally observed structures. Thermal motion of the crystals under working conditions has the potential to explain why many of these lattice minima are not observed experimentally. Lattice minima that are identified from a static crystal structure prediction can ultimately be unstable at experimental conditions through either temperature-mediated stability reranking, kinetic interconversion of multiple minima, or inaccuracies of the energy function in producing the real crystal ensemble.In this work, we explore the role of thermal motion in eliminating candidate crystal structures using fully atomistic molecular dynamics simulations. Enthalpically favorable structures with low entropy will become unfavorable at high temperatures through temperaturemediated stability reranking. Our simulations correctly identify the high temperature solid form as having a larger entropy than the low temperature form in twelve small molecule organic systems with known temperature-mediated transformations. The estimated entropy differences in the classical point-charge potential are significantly closer to experimental measurements than estimated enthalpy differences. This result suggests that entropy difference estimates are less sensitive to the complexity of the simulation potential than the corresponding enthalpy estimates. We additionally find that a cheaper harmonic approximation provides a sufficient estimate of entropic contributions in small rigid molecules. However, entropies with iv the harmonic approximation diverge from molecular dynamics-derived entropies in systems with multiple rotatable degrees of freedom or dynamically disordered crystalline structures.We additionally probe the sensitivity of the stability estimates to the energy function ...

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Section: Conclusion and Future Outlookmentioning

confidence: 98%

Section: Conclusion and Future Outlookmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Dybeck

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Modeling Ligand–Target Binding with Enhanced Sampling Simulations

Comitani

Gervasio

2018

Biomolecular Simulations in Structure‐Based Drug Discovery

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BAR‐Based Multi‐Dimensional Nonequilibrium Pulling for Indirect Construction of QM/MM Free Energy Landscapes: Varying the QM Region

Sun

Liu

2021

Advcd Theory and Sims

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The indirect free energy simulation at quantum mechanics (QM)/ molecular mechanics (MM) levels provides a feasible alternative to direct QM/MM simulations. The main idea under the indirect method is constructing a thermodynamic cycle, exploring the configurational space under a cheaper but less accurate QM level, and performing an alchemical correction to obtain the thermodynamics under an accurate but computationally demanding QM level. In the authors' previous works, a multi-dimensional nonequilibrium free energy simulation framework was developed to obtain QM/MM free energy landscapes indirectly, where the QM theory is varied but the other details of the multi-scale treatment remain unchanged. In this work, the possibility of changing the region for electronic structure calculations in the multi-scale treatment is explored. Numerical tests are performed for the conformational change in a biologically relevant peptide in vacuo and in solution, and the QM region and QM level are varied simultaneously. Unidirectional and bidirectional equilibrium perturbations are also performed for comparison. The indirect estimates from the nonequilibrium perturbation framework are almost identical to the direct results, while the indirect equilibrium estimates show obvious deviations from the direct references. They further derive the acceleration ratio of the indirect scheme to understand when the indirect scheme prevails.

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Extensive all-atom Monte Carlo sampling and QM/MM corrections in the SAMPL4 hydration free energy challenge

Cited by 52 publications

References 38 publications

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Modeling Ligand–Target Binding with Enhanced Sampling Simulations

BAR‐Based Multi‐Dimensional Nonequilibrium Pulling for Indirect Construction of QM/MM Free Energy Landscapes: Varying the QM Region

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