Explicit Hydrogen-Bond Potentials and Their Application to NMR Scalar Couplings in Proteins

Hydrogen bonds (H bonds) are fundamental for the stability, structure, and dynamics of chemically and biologically relevant systems. One of the direct means to detect H bonds in proteins is NMR spectroscopy. As H bonds are dynamic in nature, atomistic simulations offer a meaningful way to characterize and analyze properties of hydrogen bonds, provided a sufficiently accurate interaction potential is available. Here, we use explicit H-bond potentials to investigate scalar coupling constants h3JNC′ and characterize the conformational ensemble for increasingly accurate intermolecular potentials. By considering a range of proteins with different overall topology a general procedure to improve the hydrogen-bonding potential (“morphing potentials”) based on experimental information is derived. The robustness of this approach is established through explicit simulations in full solvation and comparison with experimental results. The H-bond potentials used here lead to more directional H bonds than conventional electrostatic representations employed in molecular mechanics potentials. It is found that the optimized potentials lead to H-bond geometries in remarkable agreement with previous ab initio and knowledge-based approaches to H bonds in model systems and in proteins. This suggests that, by combining theory, computation, and experimental data, H-bonding potentials can be improved and are potentially useful to better study coupling, energy transfer, and allosteric communication in proteins.