Several methods based on enhanced-sampling molecular dynamics have been proposed for studying ligand binding processes. Here, we developed a protocol that combines the advantages of steered molecular dynamics (SMD) and metadynamics. While SMD is proposed for investigating possible unbinding pathways of the ligand and identifying the preferred one, metadynamics, with the path collective variable (PCV) formalism, is suggested to explore the binding processes along the pathway defined on the basis of SMD, by using only two CVs. We applied our approach to the study of binding of two known ligands to the hypoxia-inducible factor 2α, where the buried binding cavity makes simulation of the process a challenging task. Our approach allowed identification of the preferred entrance pathway for each ligand, highlighted the features of the bound and intermediate states in the free-energy surface, and provided a binding affinity scale in agreement with experimental data. Therefore, it seems to be a suitable tool for elucidating ligand binding processes of similar complex systems.

Callea, L., Bonati, L., & Motta, S. (2021). Metadynamics-Based Approaches for Modeling the Hypoxia-Inducible Factor 2α Ligand Binding Process. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 17(7), 3841-3851 [10.1021/acs.jctc.1c00114].

Metadynamics-Based Approaches for Modeling the Hypoxia-Inducible Factor 2α Ligand Binding Process

Callea, L;Bonati, L;Motta, S
2021

Abstract

Several methods based on enhanced-sampling molecular dynamics have been proposed for studying ligand binding processes. Here, we developed a protocol that combines the advantages of steered molecular dynamics (SMD) and metadynamics. While SMD is proposed for investigating possible unbinding pathways of the ligand and identifying the preferred one, metadynamics, with the path collective variable (PCV) formalism, is suggested to explore the binding processes along the pathway defined on the basis of SMD, by using only two CVs. We applied our approach to the study of binding of two known ligands to the hypoxia-inducible factor 2α, where the buried binding cavity makes simulation of the process a challenging task. Our approach allowed identification of the preferred entrance pathway for each ligand, highlighted the features of the bound and intermediate states in the free-energy surface, and provided a binding affinity scale in agreement with experimental data. Therefore, it seems to be a suitable tool for elucidating ligand binding processes of similar complex systems.
Articolo in rivista - Articolo scientifico
Scientifica
Molecular dynamics, Steered MD, Metadynamics, Path Collective Variables, free-energy surface, ligand binding, ligand unbinding, HIF-2α
English
Callea, L., Bonati, L., & Motta, S. (2021). Metadynamics-Based Approaches for Modeling the Hypoxia-Inducible Factor 2α Ligand Binding Process. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 17(7), 3841-3851 [10.1021/acs.jctc.1c00114].
Callea, L; Bonati, L; Motta, S
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/324449
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