Molecular dynamics simulations and statistical coupling analysis of GPI12 in L. major: functional co-evolution and conservedness reveals potential drug–target sites

Singh, Shailza; Mandlik, Vineetha; Shinde, Sonali

doi:10.1039/c4mb00649f

Cited by 6 publications

(2 citation statements)

References 26 publications

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“…[40][41][42] The few studies that have examined how SCA sectors relate to dynamics have mostly focused on using SCA to predict which mutations will impact dynamics 31 or combining SCA and molecular dynamics simulations to identify coupled positions 32 or allosteric pockets for drug design. 43 There have been relatively few studies that investigated how coevolving residues identified by SCA relate to dynamic networks within proteins, although the theoretical underpinnings of SCA and molecular evolution suggest that dynamic networks that are important for protein function should be represented as sectors. One study did find a strong overlap between sectors identified by a decomposition of a covariance matrix of structural dynamics and the sectors identified by SCA.…”

Section: Introductionmentioning

confidence: 99%

Statistical Coupling Analysis Predicts Correlated Motions in Dihydrofolate Reductase

Kalmer,

Ancajas,

Cohen

et al. 2024

Preprint

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The role of dynamics in enzymatic function is a highly debated topic. Dihydrofolate reductase (DHFR), due to its universality and the depth with which it has been studied, is a model system in this debate. Myriad previous works have identified networks of residues in positions near to and remote from the active site that are involved in dynamics and others that are important for catalysis. For example, specific mutations on the Met20 loop inE. coliDHFR (N23PP/S148A) are known to disrupt millisecond-timescale motions and reduce catalytic activity. However, how and if networks of dynamically coupled residues influence the evolution of DHFR is still an unanswered question. In this study, we first identify, by statistical coupling analysis and molecular dynamic simulations, a network of coevolving residues, which possess increased correlated motions. We then go on to show that allosteric communication in this network is selectively knocked down in N23PP/S148A mutantE. coliDHFR. Finally, we identify two sites in the human DHFR sector which may accommodate the Met20 loop double proline mutation while preserving dynamics. These findings strongly implicate protein dynamics as a driving force for evolution.

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Section: Introductionmentioning

confidence: 99%

Statistical Coupling Analysis Predicts Correlated Motions in Dihydrofolate Reductase

Kalmer,

Ancajas,

Cohen

et al. 2024

Preprint

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show abstract

“…The basic assumption is that residues that display an evolutionary covariance, outside of simple evolutionary history, are energetically coupled for function and/or structure. SCA has been applied to a wide variety of proteins and in many instances, a network of energetically coupled residues has been revealed . Often these residues are located on known allosteric pathways or the predictions of SCA have suggested residues for mutation either alone or as a part of a double‐mutant cycle.…”

Section: Introductionmentioning

confidence: 99%

A network of allosterically coupled residues in the bacteriophage T4 Mre11–Rad50 complex

2016

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The Mre11-Rad50 (MR) protein complex, made up of a nuclease and ATPase, respectively, is involved in the processing of double-strand breaks as part of an intricate mechanism for their repair. Although it is clear that the MR complex is subject to allosteric regulation and that there is communication between the nuclease and ATPase active sites, the underlying mechanisms are poorly understood. We performed statistical coupling analysis on Mre11 and Rad50 to predict linked residues based on their evolutionary correlation. This analysis predicted a coevolving sector of six residues that may be allosterically coupled. The prediction was tested using double-mutant cycle analysis of nuclease and ATPase activity. The results indicate that a tyrosine residue located near the active site of Mre11 is allosterically coupled to several Rad50 residues located over 40 Å away. This allosteric coupling may be the basis for the reciprocal regulation of the ATPase and nuclease activities of the complex.

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Small design from big alignment: engineering proteins with multiple sequence alignment as the starting point

et al. 2020

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Molecular dynamics simulations and statistical coupling analysis of GPI12 in L. major: functional co-evolution and conservedness reveals potential drug–target sites

Abstract: GPI12 represents an important enzyme in the GPI biosynthetic pathway of several parasites like ‘Leishmania’.

Cited by 6 publications

References 26 publications

Statistical Coupling Analysis Predicts Correlated Motions in Dihydrofolate Reductase

Statistical Coupling Analysis Predicts Correlated Motions in Dihydrofolate Reductase

A network of allosterically coupled residues in the bacteriophage T4 Mre11–Rad50 complex

Small design from big alignment: engineering proteins with multiple sequence alignment as the starting point

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