Theoretical insights into mutation-mediated conformational changes of the GNP-bound H-RAS

Zhao, Juan; Sun, Haibo; Wang, Wei; Zhang, Lin; Chen, Jianzhong

doi:10.1016/j.cplett.2020.138042

Cited by 7 publications

(3 citation statements)

References 63 publications

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“…Therefore, any alterations in the conformational states of the switch domains will undoubtedly influence the binding and disrupt the function of HRAS. These findings are consistent with previous studies [33,73,77], further validating our current research.…”

Section: Analyses Of Gtp-and Gdp-hras Interaction Networksupporting

confidence: 94%

Conformational States of the GDP- and GTP-Bound HRAS Affected by A59E and K117R: An Exploration from Gaussian Accelerated Molecular Dynamics

Yu,

Wang,

Cui

et al. 2024

Molecules

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The HRAS protein is considered a critical target for drug development in cancers. It is vital for effective drug development to understand the effects of mutations on the binding of GTP and GDP to HRAS. We conducted Gaussian accelerated molecular dynamics (GaMD) simulations and free energy landscape (FEL) calculations to investigate the impacts of two mutations (A59E and K117R) on GTP and GDP binding and the conformational states of the switch domain. Our findings demonstrate that these mutations not only modify the flexibility of the switch domains, but also affect the correlated motions of these domains. Furthermore, the mutations significantly disrupt the dynamic behavior of the switch domains, leading to a conformational change in HRAS. Additionally, these mutations significantly impact the switch domain’s interactions, including their hydrogen bonding with ligands and electrostatic interactions with magnesium ions. Since the switch domains are crucial for the binding of HRAS to effectors, any alterations in their interactions or conformational states will undoubtedly disrupt the activity of HRAS. This research provides valuable information for the design of drugs targeting HRAS.

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Section: Analyses Of Gtp-and Gdp-hras Interaction Networksupporting

confidence: 94%

Conformational States of the GDP- and GTP-Bound HRAS Affected by A59E and K117R: An Exploration from Gaussian Accelerated Molecular Dynamics

Yu,

Wang,

Cui

et al. 2024

Molecules

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“… 54 , 55 Recently, different works verify that MSMDSs can indeed obtain rational conformational samplings of receptors, moreover MSMDSs have been extensively applied to uncover conformational transformations of receptors, binding selectivity, drug resistance, etc. 56 − 67 In the present work, three inhibitors, namely D8Q, D9T, and UO1 were chosen to study their binding selectivity toward BAZ2A/B and decipher selectivity-dependent molecular mechanism. The structures of D8Q, D9T, and UO1 were displayed in Figure 1 B–D.…”

Section: Introductionmentioning

confidence: 99%

“…In calculations of binding affinity, the entropic computation is highly changing, Duan et al proposed a more efficient method of entropic calculations, namely interaction entropy, which not only obtains rational results but also saves computational time. , Moreover, various works have been involved in successful insights into binding selectivity of small compounds toward homologous receptors with very similar sequence. − However, the conformations of receptors sampled by cMD simulations are possibly trapped at a local minimum energy well, which will generate an insufficient structural ensemble and affect statistical rationality. To relieve this sampling issue in cMD simulations, multiple short molecular dynamics simulations (MSMDSs) with various initial conformations are proposed so as to obtain better sampling efficiency than a single long trajectory. , Recently, different works verify that MSMDSs can indeed obtain rational conformational samplings of receptors, moreover MSMDSs have been extensively applied to uncover conformational transformations of receptors, binding selectivity, drug resistance, etc. − In the present work, three inhibitors, namely D8Q, D9T, and UO1 were chosen to study their binding selectivity toward BAZ2A/B and decipher selectivity-dependent molecular mechanism. The structures of D8Q, D9T, and UO1 were displayed in Figure B–D.…”

Section: Introductionmentioning

confidence: 99%

Binding Selectivity of Inhibitors toward Bromodomains BAZ2A and BAZ2B Uncovered by Multiple Short Molecular Dynamics Simulations and MM-GBSA Calculations

Wang

Yang

et al. 2021

ACS Omega

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Two Bromodomain-Containing proteins BAZ2A and BAZ2B are responsible for remodeling chromatin and regulating noncoding RNAs. As for our current studies, integration of multiple short molecular dynamics simulations (MSMDSs) with molecular mechanics generalized Born surface area (MM-GBSA) method is adopted for insights into binding selectivity of three small molecules D8Q, D9T and UO1 to BAZ2A against BAZ2B. The calculations of MM-GBSA unveil that selectivity of inhibitors toward BAZ2A and BAZ2B highly depends on the enthalpy changes and the details uncover that D8Q has better selectivity toward BAZ2A than BAZ2B, D9T more favorably bind to BAZ2B than BAZ2A, and UO1 does not show obvious selectivity toward these two proteins. The analysis of interaction network between residues and inhibitors indicates that seven residues are mainly responsible for the selectivity of D8Q, six residues for D9T and four residues provide significant contributions to associations of UO1 with two proteins. Moreover the analysis of interaction network not only reveals warm spots of inhibitor bindings to BAZ2A and BAZ2B but also unveils that common residue pairs, including (W1816, W1887), (P1817, P1888), (F1818, F1889), (V1822, V1893), (N1823, N1894),(L1826, L1897), (V1827, V1898), (F1872, F1943), (N1873, N1944) and (V1879, I1950) belonging to (BAZ2A, BAZ2B), induce mainly binding differences of inhibitors to BAZ2A and BAZ2B. Hence, insights from our current studies offer useful dynamics information relating with conformational alterations and structure-affinity relationship at atomistic levels for novel therapeutic strategies toward BAZ2A and BAZ2B.

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Molecular mechanism related to the binding of fluorophores to Mango-II revealed by multiple-replica molecular dynamics simulations

Chen

Wang

et al. 2021

Phys. Chem. Chem. Phys.

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Theoretical insights into mutation-mediated conformational changes of the GNP-bound H-RAS

Cited by 7 publications

References 63 publications

Conformational States of the GDP- and GTP-Bound HRAS Affected by A59E and K117R: An Exploration from Gaussian Accelerated Molecular Dynamics

Conformational States of the GDP- and GTP-Bound HRAS Affected by A59E and K117R: An Exploration from Gaussian Accelerated Molecular Dynamics

Binding Selectivity of Inhibitors toward Bromodomains BAZ2A and BAZ2B Uncovered by Multiple Short Molecular Dynamics Simulations and MM-GBSA Calculations

Molecular mechanism related to the binding of fluorophores to Mango-II revealed by multiple-replica molecular dynamics simulations

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