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

How Atomic Level Interactions Drive Membrane Fusion: Insights From Molecular Dynamics Simulations

This project is focused on identifying the role of key players in the membrane fusion process at the atomic level with the use of molecular dynamics simulations. Membrane fusion of apposed bilayers is one of the most fundamental and frequently occurring biological phenomena in living organisms. It is an essential step in several cellular processes such as neuronal exocytosis, sperm fusion with oocytes and intracellular fusion of organelles to name a few. Membrane fusion is a frequent process in a living organism but is still not fully understood at the atomic level in terms of the role of various factors that play a crucial part in completion of membrane fusion. Two major factors that have been identified and studied experimentally are the protein Synaptotagmin and SNAREs. In addition, Ca2+ is known to play a crucial role in this process, however the exact mechanism of action is still unknown. Prime objective of this study is to understand these interactions and the role of Ca2 + in the process at the atomic level by carrying out molecular dynamics simulations. One of the primary calculations to perform is potential of mean force (PMF) between SYT and bilayer to analyze the effect of Ca2+ on their relative affinities. 1-octanol-water partition coefficient (log Kow) of a solute is a key parameter used in the prediction of a wide variety of complex phenomena such as drug availability and bioaccumulation potential of trace contaminants. Adaptive biasing force method is applied to calculate 1-octanol partition coefficients of n-alkanes and extended to other complex systems like ionic liquids, energetic materials and chemical warfare agents. Molecular dynamics simulations show that both domains of SYT-1, C2A and C2B, once calcium bound, insert into the lipid bilayer composed of anionic phospholipids. In contrast, no insertion is observed when the domains do not have bound calcium or when the bilayer is not charged negative. Electrostatic interactions play an important role in this insertion process. Effect of calcium binding to the C2A and C2B domain on the overall electrostatics of the protein was studied by generating the ESP maps. Negative potential on the Calcium binding pocket transforms into positive potential once calcium is attached to those sites. Interaction of this positive potential surface with the negatively charged bilayer acts as a driving force for protein insertion into the bilayer. In addition, adaptive biasing force method has emerged as a powerful tool for prediction of 1-octanol water partition coefficients and is successfully implemented and optimized for n-alkanes and extended to the systems of ionic liquids, energetic materials and chemical warfare agents for which 1-octanol water partition coefficient is either not known or is difficult to measure via experimental methods

1-Octanol/water partition coefficients of n-alkanes from molecular simulations of absolute solvation free energies

The 1-octanol/water partition coefficient is an important thermodynamic variable usually employed to understand and quantify the partitioning of solutes between aqueous and organic phases. It finds widespread use in many empirical correlations to evaluate the environmental fate of pollutants as well as in the design of pharmaceuticals. The experimental evaluation of 1-octanol/water partition coefficients is an expensive and time-consuming procedure, and thus, theoretical estimation methods are needed, particularly when a physical sample of the solute may not yet be available, such as in pharmaceutical screening. 1-Octanol/water partition coefficients can be obtained from Gibbs free energies of solvation of the solute in both the aqueous and the octanol phases. The accurate evaluation of free energy differences remains today a challenging problem in computational chemistry. In order to study the absolute solvation Gibbs free energies in 1-octanol, a solvent that can mimic many properties of important biological systems, free energy calculations for n-alkanes in the range C-1-C-8 were performed using molecular simulation techniques, following the thermodynamic integration approach. In the first part of this paper, we test different force fields by evaluating their performance in reproducing pure 1-octanol properties. It is concluded that all-atom force fields can provide good accuracy but at the cost of a higher computational time compared to that of the united-atom force fields. Recent versions of united-atom force fields, such as Gromos and TraPPE, provide satisfactory results and are, thus, useful alternatives to the more expensive all-atom models. In the second part of the paper, the Gibbs free energy of solvation in 1-octanol is calculated for several n-alkanes using three force fields to describe the solutes, namely Gromos, TraPPE, and OPLS-AA. Generally, the results obtained are in excellent agreement with the available experimental data and are of similar accuracy to commonly used QSPR models. Moreover, we have estimated the Gibbs free energy of hydration for the different compounds with the three force fields, reaching average deviations from experimental data of less than 0.2 kcal/mol for the case of the Gromos force field. Finally, we systematically compare different strategies to obtain the 1-octanol/water partition coefficient from the simulations. It is shown that a fully predictive method combining the Gromos force field in the aqueous phase and the OPLS-AA/TraPPE force field for the organic phase can give excellent predictions for n-alkanes up to C-8 with an absolute average deviation of 0.1 log P units to the experimental data

How Water's Properties Are Encoded in Its Molecular Structure and Energies.

How are water's material properties encoded within the structure of the water molecule? This is pertinent to understanding Earth's living systems, its materials, its geochemistry and geophysics, and a broad spectrum of its industrial chemistry. Water has distinctive liquid and solid properties: It is highly cohesive. It has volumetric anomalies-water's solid (ice) floats on its liquid; pressure can melt the solid rather than freezing the liquid; heating can shrink the liquid. It has more solid phases than other materials. Its supercooled liquid has divergent thermodynamic response functions. Its glassy state is neither fragile nor strong. Its component ions-hydroxide and protons-diffuse much faster than other ions. Aqueous solvation of ions or oils entails large entropies and heat capacities. We review how these properties are encoded within water's molecular structure and energies, as understood from theories, simulations, and experiments. Like simpler liquids, water molecules are nearly spherical and interact with each other through van der Waals forces. Unlike simpler liquids, water's orientation-dependent hydrogen bonding leads to open tetrahedral cage-like structuring that contributes to its remarkable volumetric and thermal properties

Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations.

Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology, and identifies some of the challenges that lie therein