Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis

Abstract

In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity. Generally, mutations led to reduced binding affinity to pyrimethamine and increased conformational plasticity of DHFR. Next, dynamic residue network analysis (DRN) was applied to determine the impact of mutations and pyrimethamine binding on communication dispositions of DHFR residues. DRN revealed residues with distinctive communication profiles, distinguishing WT from drug-resistant mutants as well as pyrimethamine-bound from pyrimethamine-free models. Our results provide a new perspective on the understanding of mutation-induced drug resistance.

MDM-TASK-web: MD-TASK and MODE-TASK web server for analyzing protein dynamics

“…We and others, in a number of publications, showed the effectiveness of our DRN approach [6] , [16] , [19] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [59] , [60] . While MD-TASK has the functionality to calculate L and BC, MDM-TASK-web, now, provides further metric options.…”

“…Both MD-TASK and MODE-TASK have been highly utilized to mine protein dynamics by offering a series of novel approaches that have demonstrated their applicability in a growing number of cases [6] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] . Although both software suites are relatively easy to use, the required technical knowledge and software dependencies may act as a hurdle against more widespread usage of the tools and techniques, due to the diversity of operating systems and the relatively fast-evolving Python libraries.…”

Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations on Plasmodium falciparum Cytb-ISP Complex in the Phospholipid Bilayer Membrane

“…This portion represented the equilibrated section of the MD simulation. DRN analysis was performed to identify important residues involved in intra-protein communication in the WT and mutant systems, as applied previously to other cases [ 41 , 79 , 80 ]. L is a metric that highlights the accessibility of a residue to all other residues, while BC is indicative of the centrality (hence importance) of a residue to protein communication.…”

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter

“…Since the presence of variants causes a substantial effect in the NBD1, as evidenced from the above analysis, to analyze more closely, we used a graph theory technique to describe the effect of variants in residual communication, which is directly correlated with protein function [ 55 , 56 , 57 , 58 ]. The results are presented as average betweenness centrality (BC) and average shortest path (L), where BC indicates major residue involved in inter-domain communication, while L denotes residue reachability [ 57 , 58 ].…”