AMOEBA Force Field Predicts Accurate Hydrogen Bond Counts of Nitriles in SNase by Revealing Water-Protein Interaction in Vibrational Absorption Frequencies

Preciselyquantifying the magnitude and direction of electric fieldsin proteins has long been an outstanding challenge in understandingbiological functions. Nitrile vibrational Stark effect probes havebeen shown to be minimally disruptive to the protein structure andcan be better direct reporters of local electrostatic field in thenative state of a protein than other measures such as pK (a) shifts of titratable residues. However, interpretationsof the connection between measured vibrational energy and electricfield rely on the accurate molecular understanding of interactionsof the nitrile group and its environment, particularly from hydrogenbonding. In this work, we compared the extent of hydrogen bondingcalculated in two common force fields, the fixed charge force fieldAmber03 and polarizable force field AMOEBA, at 10 locations of cyanocysteine(CNC) in staphylococcal nuclease (SNase) against the experimentalnitrile absorption frequency in terms of full width at half-maximum(FWHM) and frequency temperature line slope (FTLS). We observed thatthe number of hydrogen bonds correlated well in AMOEBA trajectorieswith respect to both the FWHM (r = 0.88) and theFTLS (r = -0.85), whereas the correlationof Amber03 trajectories was less reliable because the Amber03 forcefield predicted more hydrogen bonds in some mutants. Moreover, wedemonstrated that contributions from the interactions between CNCand nearby water molecules were significant in AMOEBA trajectoriesbut were not predicted by Amber03. We conclude that although the nitrileabsorption peak shape could be qualitatively predicted by the fixedcharge Amber03 force field, the detailed electrostatic environmentmeasured by the nitrile probe in terms of the extent of hydrogen bondingcould only be accurately observed in the AMOEBA trajectories, wherethe permanent dipole, quadrupole, and dipole-induced-dipolepolarizable interactions were all taken into account. The significanceof this finding to the goal of accurately predicting electric fieldsin complex biomolecular environments is discussed.

Automated summary

Precisely quantifying the magnitude and direction of electric fields in proteins has been a challenge in understanding biological functions. This study compared the extent of hydrogen bonding calculated in two force fields, Amber03 and AMOEBA, at different locations in a protein and correlated it with the experimental nitrile absorption frequency. The results showed that the AMOEBA force field accurately predicted the hydrogen bonding and interactions with nearby water molecules, while the Amber03 force field had less reliable predictions. This finding is significant for accurately predicting electric fields in complex biomolecular environments.