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The process of ligand-protein unbinding is crucial in biophysics. Water is anessential part of any biological system and yet, many aspects of its roleremain elusive. Here, we simulate with state-of-the-art enhanced samplingtechniques the binding of Benzamidine to Trypsin which is a much studied andparadigmatic ligand-protein system. We use machine learning methods todetermine efficient collective coordinates for the complex non-local network ofwater. These coordinates are used to perform On-the-fly Probability EnhancedSampling simulations, which we adapt to calculate also the ligand residencetime. Our results, both static and dynamic, are in good agreement withexperiments. We find that the presence of a water molecule located at thebottom of the binding pocket allows via a network of hydrogen bonds the ligandto be released into the solution. On a finer scale, even when unbinding isallowed, another water molecule further modulates the exit time.

Water regulates the residence time of Benzamidine in Trypsin