Blind prediction of solvation free energies from the SAMPL4 challenge

Mobley, David L.; Wymer, Karisa L.; Lim, Nathan M.; Guthrie, J. Peter

doi:10.1007/s10822-014-9718-2

Cited by 149 publications

(238 citation statements)

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“…This improvement is likely a combination of two factors. First, the GAFF force field, first established in 2004,32 is now a well‐developed and well understood small molecule force field, whose solute parameters (beyond the independently derived point charges) have undergone multiple rounds of refinement and been used in multiple other free energy investigations and blind challenges 21, 27, 31, 70, 71. This extensive history of testing and development is clearly beneficial for GAFF performance, as demonstrated here and in the other recent solvation free energy studies described above.…”

Section: Resultsmentioning

confidence: 99%

“…The error analysis and significance testing suggested by Mobley et al21 was employed to evaluate the calculated solvation free energies in four solvents simulated with both the AMOEBA and GAFF force fields. The agreement of estimated solvation free energies with experiment was evaluated using mean unsigned error (MUE), mean signed error (MSE), Pearson correlation coefficient (R), coefficient of determination ( R 2 ) and Kendall's tau coefficient ( τ ) across three replicates.…”

Section: Methodsmentioning

confidence: 99%

“…Commonly, solvation free energy calculation approaches20, 21, 22, 23, 24, 25, 26 have been performed to assess force field properties. This is thanks to the availability of high accuracy experimental data, and the straightforward computational methodologies for free energy prediction.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

2016

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The effects of electronic polarization in biomolecular interactions will differ depending on the local dielectric constant of the environment, such as in solvent, DNA, proteins, and membranes. Here the performance of the AMOEBA polarizable force field is evaluated under nonaqueous conditions by calculating the solvation free energies of small molecules in four common organic solvents. Results are compared with experimental data and equivalent simulations performed with the GAFF pairwise‐additive force field. Although AMOEBA results give mean errors close to “chemical accuracy,” GAFF performs surprisingly well, with statistically significantly more accurate results than AMOEBA in some solvents. However, for both models, free energies calculated in chloroform show worst agreement to experiment and individual solutes are consistently poor performers, suggesting non‐potential‐specific errors also contribute to inaccuracy. Scope for the improvement of both potentials remains limited by the lack of high quality experimental data across multiple solvents, particularly those of high dielectric constant. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

2016

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“…Blind tests have been proposed to evaluate the ability of solvation models to predict solvation free energies. [26][27][28][29][30][31][32][33] The SMD model has presented a good performance for challenging neutral molecules in water solvent. 34 Other successful application of the SMD model was the prediction of phase separation.…”

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confidence: 99%

How Accurate is the SMD Model for Predicting Free Energy Barriers for Nucleophilic Substitution Reactions in Polar Protic and Dipolar Aprotic Solvents?

Miguel¹,

Santos²,

Silva³

et al. 2016

Journal of the Brazilian Chemical Society

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In the past seven years, the SMD (Solvent Model Density) method has been widely used by computational chemists. Thus, assessment on the reliability of this model for modeling chemical process in solution is worthwhile. In this report, it was investigated six anion-molecule nucleophilic substitution reactions in methanol and dipolar aprotic solvents. Geometry optimizations have been done at SMD/X3LYP level and single point energy calculations at CCSD(T)/TZVPP + diff level. Our results have indicated that the SMD model is not adequate for dipolar aprotic solvents, with a root of mean squared (RMS) error of 5.6 kcal mol . The classical protic to dipolar aprotic solvent rate acceleration effect was not predicted by the SMD model for the tested systems.Keywords: continuum solvation model, ion solvation, solvent effect, aromatic nucleophilic substitution, M11 functional IntroductionIn the middle of the twentieth century, several experimental studies have led to foundation of empirical rules for qualitative prediction of solvent effects on chemical reactions, authoritatively reviewed by Parker 1 in a classical paper. Nevertheless, a deeper view on solvent effects was only possible with experimental studies of gas phase ion-molecule reactions [2][3][4][5][6] and theoretical modeling of these processes. [7][8][9] It was evident from theoretical studies that solute-solvent interactions can be very strong and produce a profound effect on chemical reactivity. [10][11][12][13][14][15][16][17] On the other hand, gas phase dynamic of chemical reactions can open new mechanistic possibilities. 18,19 Among the different solvents used to conduct ionic chemical reactions, polar protic and dipolar aprotic solvents are paramount due to their property of solubilize ionic species. 20 Methanol is a polar protic solvent and its ability to solvate ions is similar to water. 21,22 In addition, it has the advantage of solubilize many organic molecules not soluble in water. Some usual dipolar aprotic solvents are dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and acetonitrile. Because anions are less solvated in these solvents, anion-molecule reactions are accelerated when transferred from protic to dipolar aprotic solvents. Our ability to describe theoretically this effect is an important goal and a challenge for continuum solvation models once requires these models be able to describe specific solutesolvent interactions. 23 Considering that the Born formula for solvation of a spherical ion of charge q and radius R into a solvent with dielectric constant ε is given by:(1) it could be noted that the use of the same "molecular cavity" for an ionic solute into a protic and dipolar aprotic solvent with high dielectric constant would lead to very similar solvation free energy of ions. A possibility to overcome this problem would be to use different molecular cavity for protic and dipolar aprotic solvents. This approach has reached some successful ten years ago using the polarizable continuum model (PCM) in the study of anion-molecule reaction...

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“…The importance of capturing the proper polarization, charges, and bonded parameters were reemphasized in the recent SAMPL blind prediction studies. [286][287][288][289][290][291][292][293][294][295].…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

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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Blind prediction of solvation free energies from the SAMPL4 challenge

Cited by 149 publications

References 27 publications

Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

How Accurate is the SMD Model for Predicting Free Energy Barriers for Nucleophilic Substitution Reactions in Polar Protic and Dipolar Aprotic Solvents?

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

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