Benchmarking biomolecular force fields for molecular dynamics simulations of native fold and enzymatic activity of SARS-CoV-2 papain-like protease

The papain-like protease (PL pro ) of the SARS-CoV-2 coronavirus is crucial for viral processing and disrupting the immune response.Therefore, it is a promising target for treating acute COVID-19 infection.Computational chemistry tools, such as molecular docking and molecular dynamics (MD) simulations, are an essential complementary technique for discovering new therapeutics.However, their results are highly dependent on scoring functions and empirical force fields (FFs).In this study, we benchmarked popular MD force fields (OPLS-AA, CHARMM27, CHARMM36, and AMBER03) to see how well they could reproduce the native fold of PL pro in water.We also took into account the impact of different water models (TIP3P, TIP4P, and TIP5P) and replicated physiological conditions by adding 100 mM NaCl and increasing the temperature to 310 K. Using various structural criteria, such as the root mean square displacement and fluctuation of backbone atoms, and the distance between the catalytic residues C(Cys111)-C(His272), we observed that most of the tested FFs effectively reproduced the native "thumb-palm-fingers" fold over short time scales of a few hundreds of nanoseconds.However, in longer MD simulations, the OPLS-AA-based setups showed better performance in accurately reproducing the folding of the catalytic domain compared to other MD setups.The latter exhibited some local unfolding of the N-terminal Ubl segment.Additionally, we explored the folding and stability of the substrate-bound holo-form of PL pro with a non-covalent inhibitor XR8-89.Our findings indicate that the OPLS-AA/TIP3P setup outperformed others, resulting in a ranking among various force fields.