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.