Can Simulations and Modeling Decipher NMR Data for Conformational Equilibria? Arginine–Vasopressin

Arginine vasopressin (AVP) has been suggested by molecular-dynamics (MD) simulations to exist as a mixture of conformations in solution. The 1H and 13C NMR chemical shifts of AVP in solution have been calculated for this conformational ensemble of ring conformations (identified from a 23 μs molecular-dynamics simulation). The relative free energies of these conformations were calculated using classical metadynamics simulations in explicit water. Chemical shifts for representative conformations were calculated using density-functional theory. Comparison with experiment and analysis of the results suggests that the 1H chemical shifts are most useful for assigning equilibrium concentrations of the conformations in this case. 13C chemical shifts distinguish less clearly between conformations, and the distances calculated from the nuclear Overhauser effect do not allow the conformations to be assigned clearly. The 1H chemical shifts can be reproduced with a standard error of less than 0.24 ppm (<2.2 ppm for 13C). The combined experimental and theoretical results suggest that AVP exists in an equilibrium of approximately 70% saddlelike and 30% clinched open conformations. Both newly introduced statistical metrics designed to judge the significance of the results and Smith and Goodman’s DP4 probabilities are presented.