Treating Entropy and Conformational Changes in Implicit Solvent Simulations of Small Molecules

Mobley, David L.; Dill, Ken A.; Chodera, John D.

doi:10.1021/jp0764384

Cited by 118 publications

(199 citation statements)

References 60 publications

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“…32 Because of the large difference in dipole moments, the Poisson-Boltzmann equation predicts a difference of 4.6 kcal/mol between the two hydration free energies. 29 Given the large experimental difference in dipole moment, why are the hydration free energies so similar? Explicit solvent comes closer to reproducing the experimental difference.…”

Section: Real Solutes Also Appear To Have Hydration Free Energy Asymmmentioning

confidence: 99%

Charge Asymmetries in Hydration of Polar Solutes

et al. 2008

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We study the solvation of polar molecules in water. The center of water's dipole moment is offset from its steric center. In common water models, the Lennard-Jones center is closer to the negatively charged oxygen than to the positively charged hydrogens. This asymmetry of water's charge sites leads to different hydration free energies of positive versus negative ions of the same size. Here, we explore these hydration effects for some hypothetical neutral solutes, and two real solutes, with molecular dynamics simulations using several different water models. We find that, like ions, polar solutes are solvated differently in water depending on the sign of the partial charges. Solutes having a large negative charge balancing diffuse positive charges are preferentially solvated relative to those having a large positive charge balancing diffuse negative charges. Asymmetries in hydration free energies can be as large as 10 kcal/mol for neutral benzene-sized solutes. These asymmetries are mainly enthalpic, arising primarily from the first solvation shell water structure. Such effects are not readily captured by implicit solvent models, which respond symmetrically with respect to charge.

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Section: Real Solutes Also Appear To Have Hydration Free Energy Asymmmentioning

confidence: 99%

Charge Asymmetries in Hydration of Polar Solutes

et al. 2008

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“…This might be a problem when comparing with experimental data for flexible molecules [71], but not for the drug-like molecules, for which no such comparison is made. The conformations used were either taken from crystal structures of proteins with the ligand of interest [69,70,72,73] or from the most stable conformation, according to a systematic conformational search at the MMFF94 level with the Spartan software [74].…”

Section: Moleculesmentioning

confidence: 99%

How accurate are continuum solvation models for drug-like molecules?

Kongsted

Söderhjelm

Ryde

2009

J Comput Aided Mol Des

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We have estimated the hydration free energy for 20 neutral drug-like molecules, as well as for three series of 6-11 inhibitors to avidin, factor Xa, and galectin-3 with four different continuum solvent approaches (the polarised continuum method the Langevin dipole method, the finite-difference solution of the Poisson equation, and the generalised Born method), and several variants of each, giving in total 24 different methods. All four types of methods have been thoroughly calibrated for a number of experimentally known small organic molecules with a mean absolute deviation (MAD) of 1-6 kJ/mol for neutral molecules and 4-30 kJ/mol for ions. However, for the drug-like molecules, the accuracy seems to be appreciably worse. The reason for this is that drug-like molecules are more polar than small organic molecules and that the uncertainty of the methods is proportional to the size of the solvation energy. Therefore, the accuracy of continuum solvation methods should be discussed in relative, rather than absolute, terms. In fact, the mean unsigned relative deviations of the best solvation methods, 0.09 for neutral and 0.05 for ionic molecules, correspond to 2-20 kJ/mol absolute error for the drug-like molecules in this investigation, or 2-3,000 in terms of binding constants. Fortunately, the accuracy of all methods can be improved if only relative energies within a series of inhibitors are considered, especially if all of them have the same net charge. Then, all except two methods give MADs of 2-5 kJ/mol (corresponding to an uncertainty of a factor of 2-7 in the binding constant). Interestingly, the generalised Born methods typically give better results than the Poison-Boltzmann methods.

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“…As an example, one may look at human red blood cells (erythrocytes), one of the most widely studied cells in nature, and point to [32] for the value E 0 = −8.4 mV, as well as [33,34] for d = 78Å. However, the value of κ for a membrane is highly contentious, due to the fact that it depends sensitively upon a large variety of biophysical attributes of the membrane, such as hydration [35], pH value [36], and structural stability [37]. In a recent review, it was reported that the value of κ in literature ranges from 1 to 40 [38].…”

Section: Discussionmentioning

confidence: 99%

A generalised Davydov-Scott model for polarons in linear peptide chains

Luo

Piette

2017

Eur. Phys. J. B

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Abstract. We present a one-parameter family of mathematical models describing the dynamics of polarons in periodic structures, such as linear polypeptides, which, by tuning the model parameter, can be reduced to the Davydov or the Scott model. We describe the physical significance of this parameter and, in the continuum limit, we derive analytical solutions which represent stationary polarons. On a discrete lattice, we compute stationary polaron solutions numerically. We investigate polaron propagation induced by several external forcing mechanisms. We show that an electric field consisting of a constant and a periodic component can induce polaron motion with minimal energy loss. We also show that thermal fluctuations can facilitate the onset of polaron motion. Finally, we discuss the bio-physical implications of our results.

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Treating Entropy and Conformational Changes in Implicit Solvent Simulations of Small Molecules

Cited by 118 publications

References 60 publications

Charge Asymmetries in Hydration of Polar Solutes

Charge Asymmetries in Hydration of Polar Solutes

How accurate are continuum solvation models for drug-like molecules?

A generalised Davydov-Scott model for polarons in linear peptide chains

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