The role of water and steric constraints in the kinetics of cavity-ligand unbinding

A key factor influencing a drug's efficacy is its residence time in the binding pocket of the host protein. Using atomistic computer simulation to predict this residence time and the associated dissociation process is a desirable but extremely difficult task due to the long timescales involved. This gets further complicated by the presence of biophysical factors such as steric and solvation effects. In this work, we perform molecular dynamics (MD) simulations of the unbinding of a popular prototypical hydrophobic cavity-ligand system using a metadynamics based approach that allows direct assessment of kinetic pathways and parameters. When constrained to move in an axial manner, we find the unbinding time to be on the order of 4000 sec. In accordance with previous studies, we find that the ligand must pass through a region of sharp dewetting transition manifested by sudden and high fluctuations in solvent density in the cavity. When we remove the steric constraints on ligand, the unbinding happens predominantly by an alternate pathway, where the unbinding becomes 20 times faster, and the sharp dewetting transition instead becomes continuous. We validate the unbinding timescales from metadynamics through a Poisson analysis, and by comparison through detailed balance to binding timescale estimates from unbiased MD. This work demonstrates that enhanced sampling can be used to perform explicit solvent molecular dynamics studies at timescales previously unattainable, obtaining direct and reliable pictures of the underlying physio-chemical factors including free energies and rate constants.Comment: 7 pages, 4 figures, supplementary PDF file, submitte

Constraining the symmetry energy content of nuclear matter from nuclear masses: a covariance analysis

Elements of nuclear symmetry energy evaluated from different energy density functionals parametrized by fitting selective bulk properties of few representative nuclei are seen to vary widely. Those obtained from experimental data on nuclear masses across the periodic table, however, show that they are better constrained. A possible direction in reconciling this paradox may be gleaned from comparison of results obtained from use of the binding energies in the fitting protocol within a microscopic model with two sets of nuclei, one a representative standard set and another where very highly asymmetric nuclei are additionally included. A covariance analysis reveals that the additional fitting protocol reduces the uncertainties in the nuclear symmetry energy coefficient, its slope parameter as well as the neutron-skin thickness in $^{208}$Pb nucleus by $\sim 50\%$. The central values of these entities are also seen to be slightly reduced.Comment: 6 pages, 2 figures, Accepted in Physical Review