The Importance of Being Exhaustive. Optimization of Bridging Structural Water Molecules and Water Networks in Models of Biological Systems

Algorithms and protocols are described for the optimization for H‐bonding of isolated singular H 2 O molecules and entire networks of H 2 O molecules. Unlike other approaches that are prone to being trapped in local energy minima, these methods rely on exhaustive searches of orientation space for the H 2 O molecules. The results are scored with the HINT hydropathic interaction model, but the algorithms should be general for any energy‐scoring computation. Two examples are provided: 1 ) the tightly‐bound H 2 O molecule 301 of HIV‐1 protease is shown to be more reasonably oriented in terms of forming H‐bonds with this method than with a molecular mechanics energy minimization method; and 2 ) the H 2 O network surrounding carbonmonoxymyoglobin is constructed and analyzed for a 1.80‐Å neutron‐diffraction structure. The H‐atom positions calculated with this method show a somewhat better agreement with the experimental results than do the H‐atom positions calculated with molecular mechanics, and both are considerably better than random.