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Accurate determination of protein:ligand standard binding free energies from molecular dynamics simulations.


ABSTRACT: Designing a reliable computational methodology to calculate protein:ligand standard binding free energies is extremely challenging. The large change in configurational enthalpy and entropy that accompanies the association of ligand and protein is notoriously difficult to capture in naive brute-force simulations. Addressing this issue, the present protocol rests upon a rigorous statistical mechanical framework for the determination of protein:ligand binding affinities together with the comprehensive Binding Free-Energy Estimator 2 (BFEE2) application software. With the knowledge of the bound state, available from experiments or docking, application of the BFEE2 protocol with a reliable force field supplies in a matter of days standard binding free energies within chemical accuracy, for a broad range of protein:ligand complexes. Limiting undesirable human intervention, BFEE2 assists the end user in preparing all the necessary input files and performing the post-treatment of the simulations towards the final estimate of the binding affinity.

SUBMITTER: Fu H 

PROVIDER: S-EPMC10082674 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Accurate determination of protein:ligand standard binding free energies from molecular dynamics simulations.

Fu Haohao H   Chen Haochuan H   Blazhynska Marharyta M   Goulard Coderc de Lacam Emma E   Szczepaniak Florence F   Pavlova Anna A   Shao Xueguang X   Gumbart James C JC   Dehez François F   Roux Benoît B   Cai Wensheng W   Chipot Christophe C  

Nature protocols 20220311 4


Designing a reliable computational methodology to calculate protein:ligand standard binding free energies is extremely challenging. The large change in configurational enthalpy and entropy that accompanies the association of ligand and protein is notoriously difficult to capture in naive brute-force simulations. Addressing this issue, the present protocol rests upon a rigorous statistical mechanical framework for the determination of protein:ligand binding affinities together with the comprehens  ...[more]

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