# Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from tauRAMD simulations Source: [Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from tauRAMD simulations]() Collection index: [llms.txt]() Data updated: 2025-10-25T19:07:52.793Z Authors: Ariane Nunes-Alves, Daria B. Kokh, Rebecca C. Wade Published: 2020-10-17T10:52:42.000Z ## Abstract The protein-ligand residence time, tau, influences molecular function in biological networks and has been recognized as an important determinant of drug efficacy. To predict tau, computational methods must overcome the problem that tau often exceeds the timescales accessible to conventional molecular dynamics (MD) simulation. Here, we apply the tau-Random Acceleration Molecular Dynamics (tauRAMD) method to a set of kinetically characterized complexes of T4 lysozyme mutants with engineered binding cavities. tauRAMD yields relative ligand dissociation rates in good accordance with experiments and thereby allows a comprehensive characterization of the ligand egress routes and determinants of tau. Although ligand dissociation by multiple egress routes is observed, we find that egress via the predominant route determines the value of tau. We also find that the presence of metastable states along egress pathways slows down protein-ligand dissociation. These physical insights could be exploited in the rational optimization of the kinetic properties of drug candidates. ## Recorded benchmark results A research result applies to its stated dataset, split, metric and evaluation configuration. Compare like-for-like settings, preserve the metric's unit and direction, and distinguish paper-reported results from independent reproduction. The best result recorded here is not a claim of exhaustive, current global coverage. ## Original sources and implementation [Original paper]() [PDF]()