Evaluation of methods to cap molecular fragments in calculating energies of interaction in avian pancreatic polypeptide

The accuracy of the determination of the energy of interaction between Phe20 and the Pro5-Thr6-Tyr7-Pro8 complex inside the hydrophobic core of avian pancreatic polypeptide was investigated using three capping strategies for molecular fractionation with conjugated caps and DFT quantum chemical calculations at the BHandHLYP/cc-pVTZ level of theory. The most accurate determination resulted from acetylation of the α-amino group combined with methyl amidation of the α-carbonyl group, with relative deviations less than 10%. Combinations of hydrogenation of the α-amino group with the replacement of the α-carbonyl group with a hydrogen and the hydrogenation of the α-amino group with methylation of the α-carbonyl group were less accurate, leading to relative deviations up to 35%. Choice of capping methods depends on the structural features of the polypeptide system, the desired accuracy, and the available computational resources.