Quantum mechanical studies of residue-specific hydrophobic interactions in p53-MDM2 binding

Quantum chemistry calculations at the levels of MP2/cc-pVDZ and MP2/cc-PVTZ have been carried out to study residue-specific interactions at the hydrophobic p53-MDM2 binding interface. The result of the calculation, based on structures from nanosecond molecular dynamics simulation, revealed that ¹⁹Phe, ²²Leu, and ²³Trp of p53 have the strongest binding interaction with MDM2 followed by ²⁶Leu and ²⁷PrO. The specific residues of MDM2 that have dominant binding interactions with p53 are specifically identified to be ⁵¹Lys, ⁵⁴Leu, ⁶²Met, ⁶⁷Tyr, ⁷²GIn, ⁹⁴Lys, ⁹⁶His, and ¹⁰⁰Tyr. The p53-MDM2 binding interaction is dominated by van der Waals interaction and to a lesser degree by electrostatic interaction. The MP2 results are in generally good agreement with those from the force field calculation while the DFT/B3LYP calculation failed to give attractive interaction energies for certain residue-residue interactions due to the lack of dispersion energy.