3DRISM Multigrid Algorithm for Fast Solvation Free Energy Calculations

In this paper we present a fast and accurate method for modeling solvation properties of organic molecules in water with a main focus on predicting solvation (hydration) free energies of small organic compounds. The method is based on a combination of (i) a molecular theory, three-dimensional reference interaction sites model (3DRISM); (ii) a fast multigrid algorithm for solving the high-dimensional 3DRISM integral equations; and (iii) a recently introduced universal correction (UC) for the 3DRISM solvation free energies by properly scaled molecular partial volume (3DRISM-UC, Palmer et al., <i>J. Phys.: Condens. Matter</i> <b>2010</b>, <i>22</i>, 492101). A fast multigrid algorithm is the core of the method because it helps to reduce the high computational costs associated with solving the 3DRISM equations. To facilitate future applications of the method, we performed benchmarking of the algorithm on a set of several model solutes in order to find optimal grid parameters and to test the performance and accuracy of the algorithm. We have shown that the proposed new multigrid algorithm is on average 24 times faster than the simple Picard method and at least 3.5 times faster than the MDIIS method which is currently actively used by the 3DRISM community (e.g., the MDIIS method has been recently implemented in a new 3DRISM implicit solvent routine in the recent release of the AmberTools 1.4 molecular modeling package (Luchko et al. <i>J. Chem. Theory Comput</i>. <b>2010</b>, <i>6</i>, 607–624). Then we have benchmarked the multigrid algorithm with chosen optimal parameters on a set of 99 organic compounds. We show that average computational time required for one 3DRISM calculation is 3.5 min per a small organic molecule (10–20 atoms) on a standard personal computer. We also benchmarked predicted solvation free energy values for all of the compounds in the set against the corresponding experimental data. We show that by using the proposed multigrid algorithm and the 3DRISM-UC model, it is possible to obtain good correlation between calculated and experimental results for solvation free energies of aqueous solutions of small organic compounds (correlation coefficient 0.97, root-mean-square deviation <1 kcal/mol)

Solvent Binding Analysis and Computational Alanine Scanning of the Bovine Chymosin–Bovine κ‑Casein Complex Using Molecular Integral Equation Theory

We demonstrate that the relative binding thermodynamics of single-point mutants of a model protein–peptide complex (the bovine chymosin–bovine κ-casein complex) can be calculated accurately and efficiently using molecular integral equation theory. The results are shown to be in good overall agreement with those obtained using implicit continuum solvation models. Unlike the implicit continuum models, however, molecular integral equation theory provides useful information about the distribution of solvent density. We find that experimentally observed water-binding sites on the surface of bovine chymosin can be identified quickly and accurately from the density distribution functions computed by molecular integral equation theory. The bovine chymosin–bovine κ-casein complex is of industrial interest because bovine chymosin is widely used to cleave bovine κ-casein and to initiate milk clotting in the manufacturing of processed dairy products. The results are interpreted in light of the recent discovery that camel chymosin is a more efficient clotting agent than bovine chymosin for bovine milk

Dynamic and Static Characteristics of Drug Dissolution in Supercritical CO₂ by Infrared Spectroscopy: Measurements of Acetaminophen Solubility in a Wide Range of State Parameters

In this work we use infrared spectroscopy to investigate solubility properties of a bioactive substance in supercritical CO₂ (scCO₂). By using acetaminophen as a model compound, we show that the method can provide high sensitivity that makes it possible to study solubility at small concentrations, up to 10^–6 mol·L^–1. This method also allows one to investigate the kinetics of the dissolution process in supercritical solvent. Our measurements at two different points of the (<i>p</i>,<i>T</i>) plane ((40 MPa, 373 K) and (40 MPa, 473 K)) have shown significant difference in the kinetic mechanisms of acetaminophen dissolution at these two states: at higher temperature the dissolution process in scCO₂ has <i>two steps</i>: (i) “fast” step when the acetaminophen concentration in scCO₂ quickly reaches (70 to 80) % of the saturation level and (ii) a subsequent “slow” step where the acetaminophen concentration slowly increases up to the saturation level. However, at lower temperature, the dissolution process has only one, “slow” step

First-Principles Calculation of the Intrinsic Aqueous Solubility of Crystalline Druglike Molecules

We demonstrate that the intrinsic aqueous solubility of crystalline druglike molecules can be estimated with reasonable accuracy from sublimation free energies calculated using crystal lattice simulations and hydration free energies calculated using the 3D Reference Interaction Site Model (3D-RISM) of the Integral Equation Theory of Molecular Liquids (IET). The solubilities of 25 crystalline druglike molecules taken from different chemical classes are predicted by the model with a correlation coefficient of <i>R</i> = 0.85 and a root mean square error (RMSE) equal to 1.45 log₁₀ <i>S</i> units, which is significantly more accurate than results obtained using implicit continuum solvent models. The method is not directly parametrized against experimental solubility data, and it offers a full computational characterization of the thermodynamics of transfer of the drug molecule from crystal phase to gas phase to dilute aqueous solution