Explicit-pH Coarse-Grained Molecular Dynamics Simulations Enable Insights into Restructuring of Intestinal Colloidal Aggregates with Permeation Enhancers

Permeation enhancers (PEs) can increase the bioavailability of drugs. The mechanisms of action of these PEs are complex, but, typically, when used for oral administration, they can transiently induce the alteration of trans- and paracellular pathways, including increased solubilization and membrane fluidity, or the opening of the tight junctions. To elucidate these mechanistic details, it is important to understand the aggregation behavior of not only the PEs themselves but also other molecules already present in the intestine. Aggregation processes depend critically on, among other factors, the charge state of ionizable chemical groups, which is affected by the pH of the system. In this study, we used explicit-pH coarse-grained molecular dynamics simulations to investigate the aggregation behavior and pH dependence of two commonly used PEs—caprate and SNAC—together with other components of fasted- and fed-state simulated intestinal fluids. We also present and validate a coarse-grained molecular topology for the bile salt taurocholate suitable for the Martini3 force-field. Our results indicate an increase in the number of free molecules as a function of the system pH and for each combination of FaSSIF/FeSSIF and PEs. In addition, there are differences between caprate and SNAC, which are rationalized based on their different molecular structures and critical micelle concentrations.

Theory and Practice of Coarse-Grained Molecular Dynamics of Biologically Important Systems

Molecular dynamics with coarse-grained models is nowadays extensively used to simulate biomolecular systems at large time and size scales, compared to those accessible to all-atom molecular dynamics. In this review article, we describe the physical basis of coarse-grained molecular dynamics, the coarse-grained force fields, the equations of motion and the respective numerical integration algorithms, and selected practical applications of coarse-grained molecular dynamics. We demonstrate that the motion of coarse-grained sites is governed by the potential of mean force and the friction and stochastic forces, resulting from integrating out the secondary degrees of freedom. Consequently, Langevin dynamics is a natural means of describing the motion of a system at the coarse-grained level and the potential of mean force is the physical basis of the coarse-grained force fields. Moreover, the choice of coarse-grained variables and the fact that coarse-grained sites often do not have spherical symmetry implies a non-diagonal inertia tensor. We describe selected coarse-grained models used in molecular dynamics simulations, including the most popular MARTINI model developed by Marrink’s group and the UNICORN model of biological macromolecules developed in our laboratory. We conclude by discussing examples of the application of coarse-grained molecular dynamics to study biologically important processes.

Modeling the Formation of Liposomes with Vinpocetine from Soy Lecithin Phospholipids by Molecular Dynamics

Introduction. Liposomal preparations have the following advantages: they protect body cells from the toxic effects of drugs; prolong the action of the drug introduced into the body; protect medicinal substances from degradation; promote the manifestation of targeted specificity due to selective penetration from blood into tissues; change the pharmacokinetics of drugs, increasing their pharmacological effectiveness; allow you to create a water-soluble form of a number of medicinal substances, thereby increasing their bioavailability. The development of liposomal forms of vinpocetine is highly relevant. Currently, when developing the composition of liposomal forms, molecular modeling methods are widely used, which are a convenient method for predicting both the properties of the membranes themselves and aspects of the interaction of membranes with small molecules or proteins.Aim. The aim of this study is to model the process of liposome assembly from soy lecithin phospholipids in the presence of vinpocetine by the molecular dynamics method; as well as predicting the distribution of vinpocetine between the internal cavity of the liposome, the phospholipid membrane, and the dispersion medium based on the simulation results.Materials and methods. To simulate the process of liposome formation, the method of coarse-grained molecular dynamics in a Martini 2.2 force field was used using the Gromacs 2016.4 program. The assembly of the simulated system - a solution of soy lecithin phospholipids in water was performed using the Internet service Charmm-GUI-> Inputgenerator-> Martinimaker-> Randombuilder.Results and discussion. The results of molecular modeling showed that the vinpocetine molecules did not penetrate into the liposome, but were adsorbed on its surface. This is due to the low solubility of vipocetin in the hydrophobic medium of the soy lecithin liposome membrane.Conclusion. It was shown that the minimum diameter of a liposome formed from purified soy lecithin is 15.3 nm. Vinpocetine does not penetrate into liposomes from purified soy lecithin, but is adsorbed on the outer surface of their membrane. The surface excess in this case, according to the results of modeling coarse-grained molecular dynamics at a temperature of 298 K in an alcohol-water medium, is 1.2 • 10-7 mol/m2.

The kinetic landscape of nucleosome assembly: A coarse-grained molecular dynamics study

The organization of nucleosomes along the Eukaryotic genome is maintained over time despite disruptive events such as replication. During this complex process, histones and DNA can form a variety of non-canonical nucleosome conformations, but their precise molecular details and roles during nucleosome assembly remain unclear. In this study, employing coarse-grained molecular dynamics simulations and Markov state modeling, we characterized the complete kinetics of nucleosome assembly. On the nucleosome-positioning 601 DNA sequence, we observe a rich transition network among various canonical and non-canonical tetrasome, hexasome, and nucleosome conformations. A low salt environment makes nucleosomes stable, but the kinetic landscape becomes more rugged, so that the system is more likely to be trapped in off-pathway partially assembled intermediates. Finally, we find that the co-operativity between DNA bending and histone association enables positioning sequence motifs to direct the assembly process, with potential implications for the dynamic organization of nucleosomes on real genomic sequences.