Molecular modelling

My current postdoctoral research topic at the Heidelberg Institute of Theoretical Studies (HITS) and Heidelberg University is focused on modelling drug-polymer interactions. Limited aqueous solubility of the drug or, active pharmaceutical ingredient (API) is one of the serious concerns at the sages of drug formulation. Various strategies are being employed to increase the solubility of the APIs, such as supercritical fluid processing, cosolvency, cocrystallization and others. Recently, interest has grown in amorphous solid dispersions (ASDs) technique, in which the API and a polymeric carrier form a homogeneous amorphous solid, which displays more favourable dissolution properties than drug formulations with crystalline APIs. In a related approach, called amorphous salt solid dispersion (ASSD), counterions are added to the ASDs, to induce the formation of an amorphous salt. The main role of a polymeric carrier is to stabilize the amorphous state and stabilize the supersaturated state in vivo, thus improve the bioavailability of the APIs.

In this project, I have employed all-atom molecular dynamics simulations to check the role of cellulosic and non-cellulosic polymeric excipients with poorly soluble Biopharmaceutics Classification System (BCS) class IV drugs. Using this approach it is possible to screen a series of polymeric excipients against API or, vice versa prior to the experiments.

Another postdoctoral research at the Heidelberg Institute of Theoretical Studies (HITS) and Heidelberg University was focused on modelling of protein-protein interactions in a phospholipid membrane using a multiresolution computational approach (Fig. 2) and studying the electron transfer pathways between two proteins at the atomic level using an empirical protocol. The aim of this project is modelling of complexes of Cytochrome P450 (CYP) enzymes and their redox partner protein, NADPH-cytochrome P450 oxidoreductase (CPR) in a membrane environment. CYPs form a large superfamily of heme proteins of which some isoforms are drug metabolizing enzymes and many are drug targets in human. However, structural details and the mechanisms of electron transfer between CPR to CYP remain unclear from experimental studies till now. A multiresolution computational approach is used for solving this aforementioned conundrum. Application of this approach has yielded an ensemble of arrangements of CYP-CPR-membrane complexes that are electron transfer competent. The present study also provides atomistic insights into electron transfer routes and the determinants of electron transfer rates which agree well with available experimental data, as well as the effects of CPR binding on substrate access to the CYP.

My postdoctoral work at the Weizmann Institute of Science, Israel was focused on understanding protein-DNA interactions using a minimalist computational technique which is capable of predicting the experimentally observed binding mode accurately. My main aim of this project was to decipher the nucleation unit for the filament formation between RecA, a DNA repair protein in prokaryotes, and a single-stranded DNA (ssDNA) coming from damaged DNA (Fig. 3). The minimum number of proteins which facilitate the filament formation of protein-ssDNA was a puzzle. In order to address this puzzle, I performed modeling of the RecA-ssDNA interactions using an in-house developed coarse grained simulation method. Information from the X-ray crystal structure was used to model the protein and ssDNA but not their interactions. The interactions between protein and ssDNA were modeled solely by electrostatic, aromatic, and repulsive energies. We found that dimeric RecA is the elementary binding unit, with higher multimeric units of RecA facilitating filament formation. Our finding (Mol. Biosyst. 2017, 13, 2697-2703) agreed well with respect to the experimental observations.