Dataset Information

Prediction of Hot Spots at Myeloid Cell Leukemia-1-Inhibitor Interface Using Energy Estimation and Alanine Scanning Mutagenesis.

ABSTRACT: Myeloid cell leukemia 1 (Mcl1) is an antiapoptotic protein that plays central role in apoptosis regulation. Also, Mcl1 has the potency to resist apoptotic cues resulting in up-regulation and cancer cell protection. A molecular probe that has the potential to specifically target Mcl1 and thereby provoke its down-regulatory activity is very essential. The aim of the current study is to probe the internal conformational dynamics of protein motions and potential binding mechanism in response to a series of picomolar range Mcl1 inhibitors using explicit-solvent molecular dynamics (MD) simulations. Subsequently, domain cross-correlation and principal component analysis was performed on the snapshots obtained from the MD simulations. Our results showed significant differences in the internal conformational dynamics of Mcl1 with respect to binding affinity values of inhibitors. Further, the binding free energy estimation, using three different samples, was performed on the MD simulations and revealed that the predicted energies (?Gmmgbsa) were in good correlation with the experimental values (?Gexpt). Also, the energies obtained using all sampling models were efficiently ranked. Subsequently, the decomposition energy analysis highlighted the major energy-contributing residues at the Mcl1 binding pocket. Computational alanine scanning performed on high energy-contributing residues predicted the hot spot residues. The dihedral angle analysis using MD snapshots on the predicted hot spot residue exhibited consistency in side chain conformational motion that ultimately led to strong binding affinity values. The findings from the present study might provide valuable guidelines for the design of novel Mcl1 inhibitors that might significantly improve the specificity for new-generation chemotherapeutic agents.

SUBMITTER: Marimuthu P

PROVIDER: S-EPMC6203182 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Prediction of Hot Spots at Myeloid Cell Leukemia-1-Inhibitor Interface Using Energy Estimation and Alanine Scanning Mutagenesis.

Marimuthu Parthiban P Singaravelu Kalaimathy K

Biochemistry 20180201 7

Myeloid cell leukemia 1 (Mcl1) is an antiapoptotic protein that plays central role in apoptosis regulation. Also, Mcl1 has the potency to resist apoptotic cues resulting in up-regulation and cancer cell protection. A molecular probe that has the potential to specifically target Mcl1 and thereby provoke its down-regulatory activity is very essential. The aim of the current study is to probe the internal conformational dynamics of protein motions and potential binding mechanism in response to a se ...[more]

PMID: 29345906

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Project description:Quantifying binding specificity and drug resistance of protein kinase inhibitors is of fundamental importance and remains highly challenging due to complex interplay of structural and thermodynamic factors. In this work, molecular simulations and computational alanine scanning are combined with the network-based approaches to characterize molecular determinants underlying binding specificities of the ABL kinase inhibitors. The proposed theoretical framework unveiled a relationship between ligand binding and inhibitor-mediated changes in the residue interaction networks. By using topological parameters, we have described the organization of the residue interaction networks and networks of coevolving residues in the ABL kinase structures. This analysis has shown that functionally critical regulatory residues can simultaneously embody strong coevolutionary signal and high network centrality with a propensity to be energetic hot spots for drug binding. We have found that selective (Nilotinib) and promiscuous (Bosutinib, Dasatinib) kinase inhibitors can use their energetic hot spots to differentially modulate stability of the residue interaction networks, thus inhibiting or promoting conformational equilibrium between inactive and active states. According to our results, Nilotinib binding may induce a significant network-bridging effect and enhance centrality of the hot spot residues that stabilize structural environment favored by the specific kinase form. In contrast, Bosutinib and Dasatinib can incur modest changes in the residue interaction network in which ligand binding is primarily coupled only with the identity of the gate-keeper residue. These factors may promote structural adaptability of the active kinase states in binding with these promiscuous inhibitors. Our results have related ligand-induced changes in the residue interaction networks with drug resistance effects, showing that network robustness may be compromised by targeted mutations of key mediating residues. This study has outlined mechanisms by which inhibitor binding could modulate resilience and efficiency of allosteric interactions in the kinase structures, while preserving structural topology required for catalytic activity and regulation.

Dataset Information

Prediction of Hot Spots at Myeloid Cell Leukemia-1-Inhibitor Interface Using Energy Estimation and Alanine Scanning Mutagenesis.

Publications

Prediction of Hot Spots at Myeloid Cell Leukemia-1-Inhibitor Interface Using Energy Estimation and Alanine Scanning Mutagenesis.

Similar Datasets

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