- Title
- Allosteric pockets and dynamic residue network hubs of falcipain 2 in mutations including those linked to artemisinin resistance
- Creator
- Okeke, Chiamaka J
- Creator
- Musyoka, Thommas M
- Creator
- Sheik Amamuddy, Olivier
- Creator
- Barozi, Victor
- Creator
- Tastan Bishop, Özlem
- Subject
- To be catalogued
- Date Issued
- 2021
- Date
- 2021
- Type
- text
- Type
- article
- Identifier
- http://hdl.handle.net/10962/476585
- Identifier
- vital:77939
- Identifier
- xlink:href="https://doi.org/10.1016/j.csbj.2021.10.011"
- Description
- 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.
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (20 pages)
- Format
- Publisher
- Elsevier
- Language
- English
- Relation
- Computational and Structural Biotechnology Journal
- Relation
- Okeke, C.J., Musyoka, T.M., Amamuddy, O.S., Barozi, V. and Bishop, Ö.T., 2021. Allosteric pockets and dynamic residue network hubs of falcipain 2 in mutations including those linked to artemisinin resistance. Computational and Structural Biotechnology Journal, 19, pp.5647-5666
- Relation
- Computational and Structural Biotechnology Journal volume 19 p. 5647 2021 2001-0370
- Rights
- Publisher
- Rights
- Use of this resource is governed by the terms and conditions of the Creative Commons CC BY-NC-ND 4.0 License (Attribution-NonCommercial-NoDerivatives 4.0 International) https://creativecommons.org/licenses/by-nc-nd/4.0/
- Rights
- Open Access
- Hits: 12
- Visitors: 13
- Downloads: 3
Collections
Sheik Amamuddy, Olivier (Dr)
Tastan Bishop, Ozlem (Prof)
SDG 03. Good Health and Well-Being
RU Department of Biochemistry, Microbiology and Bioinformatics
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|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | Allosteric pockets and dynamic residue network hubs of falcipain 2 in mutations including those linked to artemisinin resistance.pdf | 6 MB | Adobe Acrobat PDF | View Details Download |