Conformational energies of biomolecules in solution: Extending the MPCONF196 benchmark with explicit water molecules

Abstract

AbstractA prerequisite for the computational prediction of molecular properties like conformational energies of biomolecules is a reliable, robust, and computationally affordable method usually selected according to its performance for relevant benchmark sets. However, most of these sets comprise molecules in the gas phase and do not cover interactions with a solvent, even though biomolecules typically occur in aqueous solution. To address this issue, we introduce a with explicit water molecules solvated version of a gas‐phase benchmark set containing 196 conformers of 13 peptides and other relevant macrocycles, namely MPCONF196 [J. Řezáč et al., JCTC 2018, 14, 1254–1266], and provide very accurate PNO‐LCCSD(T)‐F12b/AVQZ' reference values. The novel solvMPCONF196 benchmark set features two additional challenges beyond the description of conformers in the gas phase: conformer–water and water–water interactions. The overall best performing method for this set is the double hybrid revDSDPBEP86‐D4/def2‐QZVPP yielding conformational energies of almost coupled cluster quality. Furthermore, some (meta‐)GGAs and hybrid functionals like B97M‐V and B97M‐D with a large basis set reproduce the coupled cluster reference with an MAD below 1 kcal mol . If more efficient methods are required, the composite DFT‐method rSCAN‐3c (MAD of 1.2 kcal mol) is a good alternative, and when conformational energies of polypeptides or macrocycles with more than 500–1000 atoms are in the focus, the semi‐empirical GFN2‐xTB or the MMFF94 force field (for very large systems) are recommended.