Solvation thermodynamics of organic molecules by the molecular integral equation theory : approaching chemical accuracy

The integral equation theory (IET) of molecular liquids has been an active area of academic research in theoretical and computational physical chemistry for over 40 years because it provides a consistent theoretical framework to describe the structural and thermodynamic properties of liquid-phase solutions. The theory can describe pure and mixed solvent systems (including anisotropic and nonequilibrium systems) and has already been used for theoretical studies of a vast range of problems in chemical physics / physical chemistry, molecular biology, colloids, soft matter, and electrochemistry. A consider- able advantage of IET is that it can be used to study speci fi c solute − solvent interactions, unlike continuum solvent models, but yet it requires considerably less computational expense than explicit solvent simulations

Comparative molecular field analysis using molecular integral equation theory

Recently, Güssregen et al. used solute–solvent distribution functions calculated by the 3D Reference Interaction Site Model (3DRISM) in a 3D-QSAR model to predict the binding affinities of serine protease inhibitors; this approach was referred to as Comparative Analysis of 3D RISM MAps (CARMa). [J. Chem. Inf. Model., 2017, 57, 1652-1666] Here we extend this idea by introducing probe atoms into the 3DRISM solvent model in order to directly capture other molecular interactions in addition to those related to hydration/dehydration. Benchmark results for six different protein- ligand systems show that CARMa models trained on probe atom descriptors gives consistently more accurate predictions than CoMFA, and other common QSAR approaches

A molecular reconstruction approach to sitebased 3D-RISM and comparison to GIST hydration thermodynamic maps in an enzyme active site

Computed, high-resolution, spatial distributions of solvation energy and entropy can provide detailed information about the role of water in molecular recognition. While grid inhomogeneous solvation theory (GIST) provides rigorous, detailed thermodynamic information from explicit solvent molecular dynamics simulations, recent developments in the 3D reference interaction site model (3D-RISM) theory allow many of the same quantities to be calculated in a fraction of the time. However, 3D-RISM produces atomic-site, rather than molecular, density distributions, which are difficult to extract physical meaning from. To overcome this difficulty, we introduce a method to reconstruct molecular density distributions from atomic site density distributions. Furthermore, we assess the quality of the resulting solvation thermodynamics density distributions by analyzing the binding site of coagulation Factor Xa with both GIST and 3D-RISM. We find good qualitative agreement between the methods for oxygen and hydrogen densities as well as direct solute-solvent energetic interactions. However, 3D-RISM predicts lower energetic and entropic penalties for moving water from the bulk to the binding site

Molecular theory of solvation: Methodology summary and illustrations

Integral equation theory of molecular liquids based on statistical mechanics is quite promising as an essential part of multiscale methodology for chemical and biomolecular nanosystems in solution. Beginning with a molecular interaction potential force field, it uses diagrammatic analysis of the solvation free energy to derive integral equations for correlation functions between molecules in solution in the statistical-mechanical ensemble. The infinite chain of coupled integral equations for many-body correlation functions is reduced to a tractable form for 2- or 3-body correlations by applying the so-called closure relations. Solving these equations produces the solvation structure with accuracy comparable to molecular simulations that have converged but has a critical advantage of readily treating the effects and processes spanning over a large space and slow time scales, by far not feasible for explicit solvent molecular simulations. One of the versions of this formalism, the three-dimensional reference interaction site model (3D-RISM) integral equation complemented with the Kovalenko-Hirata (KH) closure approximation, yields the solvation structure in terms of 3D maps of correlation functions, including density distributions, of solvent interaction sites around a solute (supra)molecule with full consistent account for the effects of chemical functionalities of all species in the solution. The solvation free energy and the subsequent thermodynamics are then obtained at once as a simple integral of the 3D correlation functions by performing thermodynamic integration analytically.Comment: 24 pages, 10 figures, Revie

Computergestützte Vorhersage von thermodynamischen Eigenschaften organischer Moleküle in wässrigen Lösungen

We showed that the poor accuracy of hydration thermodynamics calculations with a molecular integral equation theory, Reference Interaction Site Model (RISM), can be considerably improved with a set of molecular structural corrections. In this thesis we developed a novel hybrid RISM-based method for calculation of hydration thermodynamics, the Structural Descriptors Correction (SDC) model (RISM-SDC). The method uses a thermodynamic quantity obtained by RISM as an initial approximation and a set of corrections to decrease the error of the calculated parameter. Each correction in the RISM-SDC model can be represented as a structural descriptor (Di) multiplied by the corresponding correction coefficient (ai). One important descriptor (D1) is the dimensionless partial molar volume calculated by RISM. The rest of the structural descriptors correspond to the number of specific molecular fragments (double bonds, aromatic rings, electron-donating/withdrawing substituents, etc.). The correction coefficients {ai} are found by training the model on a set of monofunctional compounds. For the first time, we showed that the RISM-SDC model allows to achieve the chemical accuracy of solvation thermodynamics predictions within the RISM approach, that has been a challenge for over 40 years. In this thesis we demonstrated the high efficiency of the RISM-SDC model for predicting important hydration thermodynamic quantities, hydration free energy (HFE) and partial molar volume (PMV).Wir haben gezeigt, dass die geringe Genauigkeit der Berechungen zur Hydrationsthermodynamik mit der molekularen Integralgleichungstheory, Reference Interaction Site Modell (RISM), in hohem Maße verbessert werden kann durch Einführung eines Satzes molekularer struktureller Korrekturen. In dieser Arbeit entwickelten wir eine neue RISM-basierte Hybridmethode für die Berechnung von Hydrationsthermodynamik, genannt Structural Descriptors Correction (SDC) Modell (RISM-SDC). Die Methode nutzt eine thermodynamische Größe, die durch RISM erhalten wird, als initiale Näherung und einen Satz von Korrekturen um den Fehler des berechneten Parameters zu verringern. Jede Korrektur im RISM-SDC Modell kann als struktureller Deskriptor (Di) mutlipliziert mit dem zugehörigen Korrekturkoeffizenten (ai) dargestellt werden. Ein wichtiger Deskriptor (D1) ist das dimensionslose partielle molare Volumen berechnet durch RISM. Die anderen strukturellen Deskriptoren entsprechen der Anzahl der spezifischen molekularen Fragmente (Doppelbindungen, aromatische Ringe, Elektron-spendende/entziehende Substituenten, etc.). Die Korrekturkoeffizienten {ai} wurden durch Anwendung des Modells auf einen Satz monofunktionaler Verbindungen ermittelt. Erstmals konnten wir zeigen, dass das RISM-SDC Modell die chemische Genauigkeit von Lösungsthermodynamik Vorhersagen mit der RISM Methode erlaubt; dies war eine Herausforderung für über 40 Jahre. In dieser Arbeit haben wir die hohe Effizienz des RISM-SDC Modells demonstriert für die Vorhersage wichtiger thermodynamischer Größen der Hydration wie der Freien Energie der Hydration (hydration free energy, HFE) und des partiellen molaren Volumens (partial molar volume, PMV)