Understanding Pi-Pi interaction in water using mean-field QM/MM method

Abstract

The π–π interaction, one of the key factors stabilizing protein structure, is discovered to be involved in liquid–liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) in recent studies. Unlike folded proteins, π–π interaction in IDPs need to be modeled in aqueous environment, since participating residues are frequently exposed to water during LLPS. In this work, we described π–π interaction in water, combining van der Waals (vdW)-corrected density functional theory (DFT) and DFT in classical explicit solvents (DFT-CES). Comparing our results with high-level wavefunction calculations and experimental data, we obtained a reliable prediction on association free energies of benzene and phenol dimer in water. We found that solvation effect marginally modifies dimer association free energies unless direct hydrogen-bond-like interaction develops between phenols, which supports the relation with the enthalpy-entropy compensation. This research provides a fundamental understanding on the molecular driving force for the phase behavior of IDPs.