Software for Multiscale Modeling
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High performance computing codes for advanced calculations
Software for Multiscale Modeling Inc. is a comprehensive solution to address requirements for Pharmaceutical Industry, and Material Science Requirements. The software solution provided consists of a system of high performance computing codes for advanced calculations of chemical processes in solution, designed based on molecular theory of solvation stemming from the first principle statistical mechanics. A core engine to achieve solvation thermodynamics is the ThreeDimensional Reference Interaction Site Model (3DRISM). It consists of efficient and well parallelized programs for standard computational chemistry applications in solution, extending to drug development platforms, material applications, and electronic structure simulations.
RISM calculation
RISM is rooted in the integral equation theory of liquids, where in statistical modelling of distribution functions of solvent, a picture of the dynamics of the system, can be obtained. The radial distribution functions (RDFs) are probabilistic functions for locating solvent at a specific distance from any reference point, e.g. any arbitrary shaped solute molecules. This is in turn gives the solvation structure around a solute of interest.
Versatility in Application
The starting point of a RISM calculation is the Molecular OrnsteinZernike (MOZ) equation, where a solvated system can be defined in 3D space by three spatial coordinates (r) and three angles (Θ). The resulting 6dimensional equation is solved assuming spherical symmetry to get direct correlation function (effect of the first particle on the second one), and indirect correlation function (interaction of the first particle with the third one). To solve the MOZ equation, another equation, or a closure relation, is needed. There are a handful set of such closure equations available; viz. the HyperNetted Chain (HNC), Mean Spherical Approximation (MSA), KovalenkoHirata (KH), KobrynGusarovKovalenko (KGK), etc. A choice of a closure relation is case specific, although the KH closure is extensively used, as it offers better numerical stability and parallelization.
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Application of the 3DRISMKH has been extensively validated for a multitude of systems ranging from van der Waals liquid simulations to bionanomaterials property simulation in solvents. A unique nature of the 3DRISMKH theory is that it can incorporate variable ionic strength of solvation using concentrations of ions as key parameter in an otherwise very dilute solution.
A list of applications of the 3DRISMKH can be found in the scientific literature articles, the links to which are provided below.
3DRISM Theory

Chandler, D.; McCoy, J. D.; Singer, S. J. J. Chem. Phys., 1986, 85, 5971–5976. DOI: 10.1063/1.451510

Kovalenko, A.; Hirata, F. Chem. Phys. Lett., 1998, 290, 237–244. DOI: 10.1016/S00092614(98)004710

Kovalenko, A.; Hirata, F. J. Chem. Phys., 1999, 110, 10095–10112. DOI: 10.1063/1.478883

Kovalenko A., Hirata F. J. Chem. Phys., 2000, 112, 10391–10402;10403–10417. DOI: 10.1063/1.481676

Kovalenko, A. Threedimensional RISM theory for molecular liquids and solidliquid interfaces. In: Molecular Theory of Solvation. Hirata F. (Ed.), Understanding Chemical Reactivity Series. Vol. 24, Kluwer Academic Publishers, Norwell, 2003, Chapter 4, pp. 169–275.

Gusarov, S.; Ziegler, T.; Kovalenko, A. J. Phys. Chem. A, 2006, 110, 6083–6090. DOI: 10.1021/jp054344t

Gusarov, S.; Pujari B. S.; Kovalenko, A. J. Comput. Chem., 2012, 33, 1478–1494. DOI: 10.1002/jcc.22974

Kovalenko, A. Partial Molar Volumes of Proteins in Solution: Prediction by Statistical–Mechanical, 3D–RISM–KB Molecular Theory of Solvation. In: Volume Properties: Liquids, Solutions and Vapours. Wilhelm, E., Letcher T. (Eds.), Royal Society of Chemistry, Cambridge, 2015, Chapter 22, pp. 575–610. DOI: 10.1039/978178262704300575

Roy, D.; Kovalenko, A. 3DRISMKH Molecular Solvation Theory. In: Multiscale Dynamics Simulations: Nano and Nanobio Systems in Complex Environments. Salahub, D. R.; Wei, D. (Eds.), RSC Publishing, London, 2021, Chapter 9, pp. 254–286. ISBN: 9781839161780

Roy, D.; Kovalenko, A. Solvation Free Energy by 3DRISMKH Theory. In: Gibbs Energy and Helmholtz Energy: Liquids, Solutions and Vapours. Wilhelm, E.; Letcher, T. M. (Eds.) RSC Publishing, London, 2022, Chapter 6, pp. 227–237. ISBN: 9781839162015.

Roy, D.; Kovalenko, A. Biomolecular Simulations with the ThreeDimensional Reference Interaction Site Model with the KovalenkoHirata Closure Molecular Solvation Theory. Int. J. Molec. Sci., 2021, 22, 5061–14. DOI: 10.3390/ijms22105061
Solvation Free Energy and Solvent Maps with the 3DRISMKH Theory (including Ligand Mapping, Molecular Docking, and Molecular Partitioning)

Stumpe, M. C.; Blinov, N.; Wishart, D.; Kovalenko, A.; Pande, V. S. Calculation of Local Water Densities in Biological Systems – A Comparison of Molecular Dynamics Simulations and the 3DRISMKH Molecular Theory of Solvation. J. Phys. Chem. B, 2011, 115, 319–328 (Journal Cover).

Imai, T.; Miyashita, N.; Sugita, Y.; Kovalenko, A.; Hirata, F.; Kidera, A. Functionality Mapping on Internal Surfaces of Multidrug Transporter AcrB Based on Molecular Theory of Solvation: Implications for Drug Efflux Pathway. J. Phys. Chem. B, 2011, 115, 8288–8295 (Journal Cover).

Nikolic, D.; Blinov, N.; Wishart, D.; Kovalenko, A. 3DRISMDock: A New FragmentBased Drug Design Protocol. J. Chem. Theory Comput., 2012, 8, 3356–3372.

Nikolić, D.; Moffat, K. A.; Farrugia, V. M.; Kobryn, A. E.; Gusarov, S.; Wosnick, J. H.; Kovalenko, A. MultiScale Modeling and Synthesis of Polyester Ionomers. Phys. Chem. Chem. Phys., 2013, 15, 6128–6138.

Kovalenko, A. Multiscale modeling of solvation in chemical and biological nanosystems and in nanoporous materials. Pure Applied Chem., 2013, 85, 159–199 (Invited Paper).

Huang, W.J.; Blinov, N.; Wishart, D. S.; Kovalenko, A. Role of Water in Ligand Binding to MaltoseBinding Protein: Insight from a New Docking Protocol Based on the 3DRISMKH Molecular Theory of Solvation. J. Chem. Inf. Model., 2015, 55, 317–328.

Omelyan, I.; Kovalenko, A. MTSMD of biomolecules steered with 3DRISMKH mean solvation forces accelerated with generalized solvation force extrapolation. J. Chem. Theory Comput., 2015, 11, 1875–1895.

Kovalenko, A.; Gusarov, S. Multiscale methods framework: selfconsistent coupling of molecular theory of solvation with quantum chemistry, molecular simulations, and dissipative particle dynamics. Phys. Chem. Chem. Phys., 2018, 20, 2947–2969 (Invited).

Roy, D.; Kovalenko, A. Performance of 3DRISMKH in Predicting Hydration Free Energy: Effect of Solute Parameters. J. Phys. Chem. A, 2019, 123, 4087–4093.

Hinge, V. K.; Roy, D.; Kovalenko, A. Predicting skin permeability using the 3DRISMKH theory based solvation energy descriptors for a diverse class of compounds. J. ComputerAided Mol. Des., 2019, 33, 605–611.

Hinge, V. K.; Roy, D.; Kovalenko, A. Prediction of Pglycoprotein inhibitors with machine learning classification models and 3DRISMKH theory based solvation energy descriptors. J. ComputerAided Molec. Des., 2019, 33, 965–971.

Hinge, V. K.; Blinov, N.; Roy, D.; Wishart, D. S.; Kovalenko, A. The role of hydration effects in 5fluorouridine binding to SOD1: insight from a new 3DRISMKH based protocol for including structural water in docking simulations. J. ComputerAided Mol. Des., 2019, 33, 913–926.

Roy, D.; Hinge, V. K.; Kovalenko, A. To Pass or Not To Pass: Predicting the Blood−Brain Barrier Permeability with the 3DRISMKH Molecular Solvation Theory. ACS Omega, 2019, 4, 16774–16780.

Roy, D.; Hinge, V. K.; Kovalenko, A. Predicting BloodBrain Partitioning of Small Molecules Using a Novel Minimalistic DescriptorBased Approach via the 3DRISMKH Molecular Solvation Theory. ACS Omega, 2019, 4, 3055–3060.

Roy, D.; Dutta, D.; Wishart, D. S.; Kovalenko, A. Predicting PAMPA permeability using the 3DRISMKH theory: Are we there yet? J. ComputerAided Mol. Des., 2021, 35, 261–269.