Modern non-polarizable force fields diverge in modeling the enzyme-substrate complex of a canonical serine protease

Classical molecular dynamics simulation is a powerful and established method of modern computational chemistry. Being able to obtain accurate information on molecular behavior is crucial to get valuable insights into structure-function relationships that translate into fundamental findings and practical applications. Active sites of enzymes are known to be particularly intricate, therefore, simpler non-polarizable force fields may provide an inaccurate description. In this work, we addressed this hypothesis in a case of a canonical serine triad protease trypsin in its complex with a substrate-mimicking inhibitor. We tested six modern and popular force fields to find that significantly diverging results may be obtained. Amber FB-15 and OPLS-AA/M turned out to model the active site incorrectly. Amber ff19sb and ff15ipq demonstrated mixed performance. The best performing force fields were CHARMM36m and Amber ff99sb-ildn, therefore, they are recommended for use with this and related systems. We speculate that a similar lack of cross-force field convergence may be characteristic of other enzymatic systems. Therefore, we advocate for careful consideration of different force fields in any study within the field of computational enzymology.

Automated summary

Classical molecular dynamics simulation is a powerful tool in computational chemistry, but accurate force fields are crucial for studying complex enzymatic systems. In this study, six force fields were tested on a serine triad protease trypsin complex, with diverging results. The best performing force fields were recommended for use in similar systems, and it is suggested to carefully consider force field choice in computational enzymology studies.