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

Okeke, Chiamaka Jessica; Musyoka, Thommas M.; Amamuddy, Olivier Sheik; Barozi, Victor; Bishop, Özlem Taştan

doi:10.1016/j.csbj.2021.10.011

Cited by 15 publications

(39 citation statements)

References 98 publications

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“…Factoring in the size of the protein, we calculated and analyzed the hubs for each metric for 2, 3, 4, and 5% and identified that the global top 4% residue data were the most informative. As previously established, 38 4% hub data for each metric are presented as a heat map. Analysis of each of the heat maps is detailed in the following subsections.…”

Section: Resultsmentioning

confidence: 99%

“…It is used to identify key allosteric residues 57 as well as mutation and ligand-induced residue network changes in a variety of proteins. 38 , 41 , 58 , 59 …”

Section: Resultsmentioning

confidence: 99%

“…Visual inspection of the residue mapping to the 3D KatG WT structure, unexpectedly, showed that the identified BC hubs form large hub ensembles as communication regions rather than clearly defined single communication paths, as identified in our previous studies. 37 , 38 These hubs are mostly located at or around the interface region ( Figure S5 ). In addition to conferring structural stability, 61 protein interface residues are also known to be involved in inter- and intraprotein communication.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we showed that high centrality nodes (hubs) of averaged CC values occur within the protein core. 37 , 38 Mapping the hubs to the 3D protein structures exhibited that all global top 4% averaged CC hubs are primarily located in the center of the protein, specifically in the interface area and hook region of the dimerization domain ( Figure 10 ). The persistent CC hubs are identified as Asn44, Leu45, Val47, Leu48, His49, Ala621, and Glu703.…”

Section: Resultsmentioning

confidence: 99%

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Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics

et al. 2022

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Resistance mutations in Mycobacterium tuberculosis ( Mtb ) catalase peroxidase protein (KatG), an essential enzyme in isoniazid (INH) activation, reduce the sensitivity of Mtb to first-line drugs, hence presenting challenges in tuberculosis (TB) management. Thus, understanding the mutational imposed resistance mechanisms remains of utmost importance in the quest to reduce the TB burden. Herein, effects of 11 high confidence mutations in the KatG structure and residue network communication patterns were determined using extensive computational approaches. Combined traditional post-molecular dynamics analysis and comparative essential dynamics revealed that the mutant proteins have significant loop flexibility around the heme binding pocket and enhanced asymmetric protomer behavior with respect to wild-type (WT) protein. Heme contact analysis between WT and mutant proteins identified a reduction to no contact between heme and residue His270, a covalent bond vital for the heme-enabled KatG catalytic activity. Betweenness centrality calculations showed large hub ensembles with new hubs especially around the binding cavity and expanded to the dimerization domain via interface in the mutant systems, providing possible compensatory allosteric communication paths for the active site as a result of the mutations which may destabilize the heme binding pocket and the loops in its vicinity. Additionally, an interesting observation came from Eigencentrality hubs, most of which are located in the C-terminal domain, indicating relevance of the domain in the protease functionality. Overall, our results provide insight toward the mechanisms involved in KatG-INH resistance in addition to identifying key regions in the enzyme functionality, which can be used for future drug design.

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Section: Resultsmentioning

confidence: 99%

“…It is used to identify key allosteric residues 57 as well as mutation and ligand-induced residue network changes in a variety of proteins. 38 , 41 , 58 , 59 …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics

et al. 2022

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“…Structural modeling combined with network theory has been widely exploited in studying protein topology, dynamics and allostery [ 26 – 28 ]. Dynamic network modeling of conformational ensembles has been proven as an efficient approach to describe structural and dynamic changes associated with mutational effects in complex protein systems [ 29 – 32 ]. Central to these approaches is characterization of conformational protein dynamics and mutation-induced changes in the protein equilibrium ensembles which is fundamental to understanding the physical basis of the effects of missense variants [ 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

Dissecting mutational allosteric effects in alkaline phosphatases associated with different Hypophosphatasia phenotypes: An integrative computational investigation

Xiao

Zhou²,

Song³

et al. 2022

PLoS Comput Biol

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Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone mineralization and is highly variable in its clinical phenotype. The disease occurs due to various loss-of-function mutations in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). In this work, a data-driven and biophysics-based approach is proposed for the large-scale analysis of ALPL mutations-from nonpathogenic to severe HPPs. By using a pipeline of synergistic approaches including sequence-structure analysis, network modeling, elastic network models and atomistic simulations, we characterized allosteric signatures and effects of the ALPL mutations on protein dynamics and function. Statistical analysis of molecular features computed for the ALPL mutations showed a significant difference between the control, mild and severe HPP phenotypes. Molecular dynamics simulations coupled with protein structure network analysis were employed to analyze the effect of single-residue variation on conformational dynamics of TNSALP dimers, and the developed machine learning model suggested that the topological network parameters could serve as a robust indicator of severe mutations. The results indicated that the severity of disease-associated mutations is often linked with mutation-induced modulation of allosteric communications in the protein. This study suggested that ALPL mutations associated with mild and more severe HPPs can exert markedly distinct effects on the protein stability and long-range network communications. By linking the disease phenotypes with dynamic and allosteric molecular signatures, the proposed integrative computational approach enabled to characterize and quantify the allosteric effects of ALPL mutations and role of allostery in the pathogenesis of HPPs.

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New insights of falcipain 2 structure from Plasmodium falciparum 3D7 strain

Chakraborty

Alam

Biswas

2022

Biochemical and Biophysical Research Communications

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

Abstract: Graphical abstract

Cited by 15 publications

References 98 publications

Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics

Deciphering Isoniazid Drug Resistance Mechanisms on Dimeric Mycobacterium tuberculosis KatG via Post-molecular Dynamics Analyses Including Combined Dynamic Residue Network Metrics

Dissecting mutational allosteric effects in alkaline phosphatases associated with different Hypophosphatasia phenotypes: An integrative computational investigation

New insights of falcipain 2 structure from Plasmodium falciparum 3D7 strain

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