Allosteric pockets and dynamic residue network hubs of falcipain 2 in mutations including those linked to artemisinin resistance

Chiamaka Jessica Okeke; Thommas Mutemi Musyoka; Olivier Sheik Amamuddy; Victor Barozi; Özlem Tastan Bishop

doi:10.1016/j.csbj.2021.10.011

Allosteric pockets and dynamic residue network hubs of falcipain 2 in mutations including those linked to artemisinin resistance

Comput Struct Biotechnol J. 2021 Oct 8:19:5647-5666. doi: 10.1016/j.csbj.2021.10.011. eCollection 2021.

Authors

Chiamaka Jessica Okeke¹, Thommas Mutemi Musyoka¹, Olivier Sheik Amamuddy¹, Victor Barozi¹, Özlem Tastan Bishop¹

Affiliation

¹ Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Makhanda 6140, South Africa.

Abstract

Continually emerging resistant strains of malarial parasites to current drugs present challenges. Understanding the underlying resistance mechanisms, especially those linked to allostery is, thus, highly crucial for drug design. This forms the main concern of the paper through a case study of falcipain 2 (FP-2) and its mutations, some of which are linked to artemisinin (ART) drug resistance. Here, we applied a variety of in silico approaches and tools that we developed recently, together with existing computational tools. This included novel essential dynamics and dynamic residue network (DRN) analysis algorithms. We identified six pockets demonstrating dynamic differences in the presence of some mutations. We observed striking allosteric effects in two mutant proteins. In the presence of M245I, a cryptic pocket was detected via a unique mechanism in which Pocket 2 fused with Pocket 6. In the presence of the A353T mutation, which is located at Pocket 2, the pocket became the most rigid among all protein systems analyzed. Pocket 6 was also highly stable in all cases, except in the presence of M245I mutation. The effect of ART linked mutations was more subtle, and the changes were at residue level. Importantly, we identified an allosteric communication path formed by four unique averaged BC hubs going from the mutated residue to the catalytic site and passing through the interface of three identified pockets. Collectively, we established and demonstrated that we have robust tools and a pipeline that can be applicable to the analysis of mutations.

Keywords: Allostery; Artemisinin; Centrality; Drug resistance; Dynamic residue network; Falcipains; MD-TASK; MDM-TASK-web; Missense mutations; Pocket identification; Residue contact maps.