Established DFT methods calculation of conjugation disturbed in the presence of torsional hyperconjugation

Abstract

Accurate treatment of amide resonance is important in electronic structure calculation of protein, for Resonance-Assisted Hydrogen Bonding in the hydrogen bonded chains of backbone amides of protein secondary structures such as beta sheets and alpha helices is determined by amide resonance. Variation in amide resonance is the means by which the hydrogen bonding in these chains is cooperative. Amide carbonyl orbitals are revealed by Natural Bond Orbital, NBO, analysis to substantially maintain sigma/pi separation in the presence of torsional hyperconjugative interactions with wavefunction methods but not with established Density Functional Theory, DFT, methods. This DFT error is most pronounced with small basis sets such as are used with DFT for proteins to reduce the basis function count. This error disturbs calculation of a range of amide donor-acceptor and steric interactions. This finding has important implications for the selection of electronic structure methods and basis sets for protein calculations. For example, great caution is needed in interpreting the results of applying established DFT methods to proteins containing any beta sheets. We recommend that every protein DFT calculation be accompanied by NBO assessment of maintenance of amide carbonyl sigma/pi separation and absence of carbonyl bond bending. Further, we propose that these metrics be standard benchmarks of electronic structure methods and basis sets.