Computation Of Solvation Free Energies Research Articles

Accuracy, precision, and efficiency of nonequilibrium alchemical methods for computing free energies of solvation. I. Bidirectional approaches.

In the context of molecular dynamics simulations, alchemical approaches based on nonequilibrium techniques are recently emerging as a powerful method for the computation of solvation free energy of druglike compounds. Here, we present a rigorous and extensive analysis of the accuracy and precision of the method as a function of the parameters qualifying the nonequilibrium alchemical protocol (e.g., number and length of the nonequilibrium trajectories and decoupling or recoupling alchemical schedule) on a selection of drug-size organic compounds characterized by a nontrivial conformational free energy landscape. The study is organized in two contributions. The first paper includes a detailed description of method and of the conformational behavior of molecular systems. Results are focused on the accuracy and precision bidirectional estimates of solvation free energy, notably those based on the so-called Bennett acceptance ratio. In the second paper, unidirectional estimates for solvation free energy are analyzed in depth.

Carbon nanotube as a carrier in drug delivery system for carnosine dipeptide: A computer simulation study

Biological application of carbon nanotube in drug delivery is our main concern in this investigation. For this purpose interaction of carnosine and carbon nanotube was studied in both gas phase and separately in aqueous media. Three possible interactions of carnosine dipeptide with (5,5) carbon nanotube in physiological media were considered. At first step each species were modeled using quantum mechanical calculations, in the next step, their properties in aqueous solution were studied by applying Monte Carlo simulations. The results of density functional calculations in gas phase showed that interaction of zwitterion of carnosine with carbon nanotube via NH3+ had relatively higher interaction energy than the other complexes. Computation of solvation free energies in water showed functionalization with carnosine enhanced the solubility of carbon nanotube significantly that improve the medicinal applications of these materials. Calculation of complexation free energies indicated that zwitterion of carnosine with carbon nanotube via NH3+ produced the most stable complex in aqueous solution. This tendency could be observed in gas and liquid phase similarly.

Fast Computation of Solvation Free Energies with Molecular Density Functional Theory: Thermodynamic-Ensemble Partial Molar Volume Corrections.

Molecular density functional theory (MDFT) offers an efficient implicit-solvent method to estimate molecule solvation free-energies, whereas conserving a fully molecular representation of the solvent. Even within a second-order approximation for the free-energy functional, the so-called homogeneous reference fluid approximation, we show that the hydration free-energies computed for a data set of 500 organic compounds are of similar quality as those obtained from molecular dynamics free-energy perturbation simulations, with a computer cost reduced by 2-3 orders of magnitude. This requires to introduce the proper partial volume correction to transform the results from the grand canonical to the isobaric-isotherm ensemble that is pertinent to experiments. We show that this correction can be extended to 3D-RISM calculations, giving a sound theoretical justification to empirical partial molar volume corrections that have been proposed recently.

Is the Isodesmic Reaction Approach a Better Model for Accurate Calculation of pK a of Organic Superbases? A Computational Study

The acid-base dissociation constant (p<i>K</i> _a) can be related to the solubility and binding of drugs. However, measuring accurate p<i>K</i> _a values is a challenging task. In this study, we have examined the p<i>K</i> _a of various organic superbases: naphthalenes, cyclic guanidines, vinamidines, and acyclic guanidines computationally. We have calculated the p<i>K</i> _a of such superbases by employing two methods: a conventional thermodynamic cycle and a second method based on an isodesmic reaction. The thermodynamic cycle involves computation of solvation free energy by using gas-phase free energy and the difference in solvation free energies (∆G_solv) between products and reactants. Calculations performed with the isodesmic reaction approach do not use the free energy of solvation; hence, the accuracy of the approach is less sensitive to solvent molecules and global charges of the calculated species. The root-mean-square errors (RMSE) predict that the p<i>K</i> _a of the studied organic superbases are more accurate when calculated with the isodesmic reaction approach.

A quasilinear RISM approach for the computation of solvation free energy of ionic species

A linearized RISM technique is developed to treat free energies of hydrated ions. The solvent response on the solute is calculated with the introduction of an empirical repulsive bridge function. The solvent electrostatic potential is approximated by a linear dependence on the solute charge. The approximating coefficients are derived by fitting the electrostatic energy of solvent, that is in turns computed by the charging procedure. For a series of monovalent polyatomic cations and anions the method provides free energies deviating by few percent from the experimental data.

Linear scaling molecular orbital calculations of biological systems using the semiempirical divide and conquer method

A “linear-scaling revolution” is occurring in quantum chemistry. This development is allowing for the first time the routine examination of large molecular assembles (e.g., proteins and DNA in water) using electronic structure methods. One of these approaches is the divide and conquer method and, in this article, we review the implementation of this approach for semiempirical Hamiltonians. This is then followed by brief reviews of three application areas. First, we will discuss the charge distribution of biological molecules in solution as described by quantum mechanics. In particular, the role polarization and charge transfer plays in affecting the charge distribution of proteins will be discussed. Next, we will examine the energetic consequences of charge transfer and polarization on biomolecular solvation. The final section will describe the computation of solvation free energies using a combined divide and conquer/Poisson–Boltzmann approach. The application of linear scaling quantum mechanical methods to biology is only just beginning, but the future is very bright, and it is our opinion that quantum mechanics will have a profound influence on our understanding of biological systems in the coming years. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 1494–1504, 2000

Prediction of Solvation Free Energies of Small Organic Molecules: Additive-Constitutive Models Based on Molecular Fingerprints and Atomic Constants

Solvation free energy is an important molecular characteristic useful in drug discovery because it represents the desolvation cost of a ligand binding to a receptor. Most of the recent developments in the estimation of solvation free energy require the use of molecular mechanics and dynamics calculations. Group contribution methods have been rarely used in the past for calculating solvation free energy because automated prediction methods have not been developed in this regard. As an aid to combinatorial library design, we explored rapid and accurate means of computing solvation free energies from the covalent structures of organic molecules and compared the results on a test set with the GB/SA solvation model. Two independent additive-constitutive QSPR methods have been developed for the computation of solvation free energy. The first is a QSPR model (HLOGS) derived using a technique that uses the counts of distinct/similar fragments and substructures for each molecule as variables in a PLS regression. T...

A new definition of cavities for the computation of solvation free energies by the polarizable continuum model

A set of rules for determining the atomic radii of spheres used to build the molecular cavities in continuum solvation models are presented. The procedure is applied to compute the hydration free energy for molecules containing H, C, N, O, F, P, S, Cl, Br, and I at a computational level (Hartree–Fock with a medium size basis set) allowing the study of relatively large systems. The optimized radii reduce the mean error with respect to the experimental solvation energies below 0.20 kcal/mol for a set of 43 neutral solutes and around 1 kcal/mol for 27 ions. Moreover the correct trends are observed for the solvation energies of homolog series, like the series ammonia–trimethylamine, that are not correctly reproduced by usual solvation models.