Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling

2017 ◽  
Vol 19 (44) ◽  
pp. 30239-30248 ◽  
Author(s):  
Jianzhong Chen ◽  
Jinan Wang ◽  
Weiliang Zhu
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Anaplastic Lymphoma Kinase ◽  
Drug Target ◽  
Umbrella Sampling ◽  
Free Energy Perturbation ◽  
Drug Resistant ◽  
Anaplastic Lymphoma ◽  
Energy Perturbation ◽  
Different Levels

Anaplastic lymphoma kinase (ALK) has been regarded as a promising drug target in the treatment of tumors and the mutation L1196M induces different levels of drug resistance toward the existing inhibitors.

scholarly journals An Improved Free Energy Perturbation FEP+ Sampling Protocol for Flexible Ligand-Binding Domains

2019 ◽  
Author(s):  
Filip Fratev ◽  
suman sirimulla
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Conformational Changes ◽  
Structural Changes ◽  
Binding Mode ◽  
Sampling Time ◽  
Free Energy Perturbation ◽  
Sampling Protocol ◽  
Sampling Schemes ◽  
Energy Perturbation

Recent improvements to free energy perturbation (FEP) calculations, especiallyFEP+, established their utility for pharmaceutical lead optimization. However, to dateFEP has typically been helpful only when (1) high-quality X-ray data is available and(2) the target protein does not undergo significant conformational changes. Also, alack of systematic studies on determining an adequate sampling time is often one ofthe primary limitations of FEP calculations. Herein, we propose a modified versionof the FEP/REST (i.e., replica exchange with solute tempering) sampling protocol,based on systematic studies on several targets by probing a large number of permutations with different sampling schemes. Improved FEP+ binding affinity predictions for regular flexible-loop (F-loop) motions and considerable structural changes can be obtained by extending the pre-REST sampling time from 0.24 ns to 5 ns/λand 2×10 ns/λ, respectively. We obtained much more precise ∆∆G calculations of the individual perturbations, including the sign of the transformations and less error. We extended the REST simulations from 5 ns to 8 ns to achieve reasonable free energy convergence.Implementing REST to the entire ligand as opposed to solely the perturbed region, and also some important flexible protein residues (pREST region) in ligand binding domain (LBD) , also considerably improved the FEP+ results in most of the studied cases. Preliminary molecular dynamics (MD) runs were useful for establishing the correct binding mode of the compounds and thus precise alignment for FEP+.<br>

scholarly journals An Improved Free Energy Perturbation FEP+ Sampling Protocol for Flexible Ligand-Binding Domains

2019 ◽  
Author(s):  
Filip Fratev ◽  
suman sirimulla
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Conformational Changes ◽  
Structural Changes ◽  
Binding Mode ◽  
Sampling Time ◽  
Free Energy Perturbation ◽  
Sampling Protocol ◽  
Sampling Schemes ◽  
Energy Perturbation

Recent improvements to free energy perturbation (FEP) calculations, especiallyFEP+, established their utility for pharmaceutical lead optimization. However, to dateFEP has typically been helpful only when (1) high-quality X-ray data is available and(2) the target protein does not undergo significant conformational changes. Also, alack of systematic studies on determining an adequate sampling time is often one ofthe primary limitations of FEP calculations. Herein, we propose a modified versionof the FEP/REST (i.e., replica exchange with solute tempering) sampling protocol,based on systematic studies on several targets by probing a large number of permutations with different sampling schemes. Improved FEP+ binding affinity predictions for regular flexible-loop (F-loop) motions and considerable structural changes can be obtained by extending the pre-REST sampling time from 0.24 ns to 5 ns/λand 2×10 ns/λ, respectively. We obtained much more precise ∆∆G calculations of the individual perturbations, including the sign of the transformations and less error. We extended the REST simulations from 5 ns to 8 ns to achieve reasonable free energy convergence.Implementing REST to the entire ligand as opposed to solely the perturbed region, and also some important flexible protein residues (pREST region) in ligand binding domain (LBD) , also considerably improved the FEP+ results in most of the studied cases. Preliminary molecular dynamics (MD) runs were useful for establishing the correct binding mode of the compounds and thus precise alignment for FEP+.<br>

scholarly journals An Improved Free Energy Perturbation FEP+ Sampling Protocol for Flexible Ligand-Binding Domains

2018 ◽  
Author(s):  
Filip Fratev ◽  
Suman Sirimulla
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Conformational Changes ◽  
Structural Changes ◽  
Binding Mode ◽  
Sampling Time ◽  
Free Energy Perturbation ◽  
Sampling Protocol ◽  
Sampling Schemes ◽  
Energy Perturbation

Recent improvements to free energy perturbation (FEP) calculations, especiallyFEP+, established their utility for pharmaceutical lead optimization. However, to dateFEP has typically been helpful only when (1) high-quality X-ray data is available and(2) the target protein does not undergo significant conformational changes. Also, alack of systematic studies on determining an adequate sampling time is often one ofthe primary limitations of FEP calculations. Herein, we propose a modified versionof the FEP/REST (i.e., replica exchange with solute tempering) sampling protocol,based on systematic studies on several targets by probing a large number of permutations with different sampling schemes. Improved FEP+ binding affinity predictions for regular flexible-loop (F-loop) motions and considerable structural changes can be obtained by extending the pre-REST sampling time from 0.24 ns to 5 ns/λand 2×10 ns/λ, respectively. We obtained much more precise ∆∆G calculations of the individual perturbations, including the sign of the transformations and less error. We extended the REST simulations from 5 ns to 8 ns to achieve reasonable free energy convergence.Implementing REST to the entire ligand as opposed to solely the perturbed region, and also some important flexible protein residues (pREST region) in ligand binding domain (LBD) , also considerably improved the FEP+ results in most of the studied cases. Preliminary molecular dynamics (MD) runs were useful for establishing the correct binding mode of the compounds and thus precise alignment for FEP+.<br>

scholarly journals Free energy perturbation calculations on binding and catalysis after mutating threonine 220 in subtilisin

1991 ◽  
Vol 266 (18) ◽  
pp. 11801-11809
Author(s):  
N. Mizushima ◽  
D. Spellmeyer ◽  
S. Hirono ◽  
D. Pearlman ◽  
P. Kollman
Keyword(s):  
Free Energy ◽  
Free Energy Perturbation ◽  
Energy Perturbation

scholarly journals Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations

2021 ◽  
Vol 7 (3) ◽  
pp. 467-475 ◽  
Author(s):  
Chun-Hui Zhang ◽  
Elizabeth A. Stone ◽  
Maya Deshmukh ◽  
Joseph A. Ippolito ◽  
Mohammad M. Ghahremanpour ◽  
...  
Keyword(s):  
Free Energy ◽  
Free Energy Perturbation ◽  
Main Protease ◽  
Energy Perturbation
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