ArticleCurrent research in structural biology2021
Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from τRAMD simulations.
Article in Current research in structural biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 59 citations in OpenAlex.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The protein-ligand residence time, τ, influences molecular function in biological networks and has been recognized as an important determinant of drug efficacy. To predict τ, computational methods must overcome the problem that τ often exceeds the timescales accessible to conventional molecular dynamics (MD) simulation. Here, we apply the τ-Random Acceleration Molecular Dynamics (τRAMD) method to a set of kinetically characterized complexes of T4 lysozyme mutants with small, engineered binding cavities. τRAMD yields relative ligand dissociation rates in good accordance with experiments across this diverse set of complexes that differ with regard to measurement temperature, ligand identity, protein mutation and binding cavity. τRAMD thereby allows a comprehensive characterization of the ligand egress routes and determinants of τ. Although ligand dissociation by multiple egress routes is observed, we find that egress via the predominant route determines the value of τ. We also find that the presence of a greater number of metastable states along egress pathways leads to slower protein-ligand dissociation. These physical insights could be exploited in the rational optimization of the kinetic properties of drug candidates.
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