Free energy simulations for protein ligand binding and stability

El Hage, Krystel and Mondal, Padmabati and Meuwly, Markus. (2018) Free energy simulations for protein ligand binding and stability. Molecular Simulation, 44 (13-14, Special Issue: Free Energy Simulations II). pp. 1044-1061.

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Official URL: https://edoc.unibas.ch/94223/

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We summarize several computational techniques to determine relative free energies for condensed-phase systems. The focus is on practical considerations which are capable of making direct contact with experiments. Particular applications include the thermodynamic stability of apo- and holo-myoglobin, insulin dimerization free energy, ligand binding in lysozyme, and ligand diffusion in globular proteins. In addition to provide differential free energies between neighboring states, converged umbrella sampling simulations provide insight into migration barriers and ligand dissociation barriers and analysis of the trajectories yield additional insight into the structural dynamics of fundamental processes. Also, such simulations are useful tools to quantify relative stability changes for situations where experiments are difficult. This is illustrated for NO-bound myoglobin. For the dissociation of benzonitrile from lysozyme it is found that long umbrella sampling simulations are required to approximately converge the free energy profile. Then, however, the resulting differential free energy between the bound and unbound state is in good agreement with estimates from molecular mechanics with generalized Born surface area simulations. Furthermore, comparing the barrier height for ligand escape suggests that ligand dissociation contains a non-equilibrium component.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Physikalische Chemie (Meuwly)
UniBasel Contributors:Meuwly, Markus
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Taylor & Francis
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Apr 2023 11:47
Deposited On:03 Apr 2023 09:23

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