AMOEBA Polarizable Atomic Multipole Force Field Parameters for Flavins

Computation of redox potential of cofactors in biological systems requires an accurate description of the interaction between the redox cofactors and the biomolecular environment and extensive conformational sampling. Seeking to achieve a quantitative leap in redox potential evaluation for flavoproteins, we report here the calibration of sets of parameters to describe flavin molecules in various redox states in the framework of AMOEBA, a multipolar and polarizable force field. We calibrate both the isoalloxazine ring in the five biologically relevant redox states and the polyol chain needed to describe riboflavin or flavin adenine dinucleotide molecules. We propose a delineated, step-by-step protocol to accurately account for the physical effects at play. We provide evidence that these parameters produce stable conformations in agreement with quantum chemistry (DFT) calculations. The newly derived AMOEBA force field allows to compute interaction energies of lumiflavin with water molecules and amino acids in very good agreement with quantum chemistry calculations, with a net improvement with respect to a monopolar nonpolarizable force field. Finally, as a first application, we compute redox free energy of half-reactions for two redox couples of lumiflavin in water. The values obtained are once again in better agreement with DFT values than those obtained with a standard classical force field.