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

Abstract

Arginine vasopressin (AVP) has been suggested by molecular-dynamics (MD) simulations to exist as a mixture of conformations in solution. The (1)H and (13)C 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 (1)H chemical shifts are most useful for assigning equilibrium concentrations of the conformations in this case. (13)C 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 (1)H chemical shifts can be reproduced with a standard error of less than 0.24 ppm (<2.2 ppm for (13)C). 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.

Conformation and Dynamics of Human Urotensin II and Urotensin Related Peptide in Aqueous Solution

“…However, the correlation within the calculated sets of 13 C shifts is too high to give unambiguously distinguishable models ( Figure S8). This was also found for AVP 61 and is further discussed in the SI.…”

“…Analogous experiments for URP in SDS micelles suggested a very similar structure. 31 We now report unrestrained molecular dynamics (MD) simulations of human UII and URP with the Amber ff99sb force field on extended time scales (see Table S1 and Figures S1-S6 61 Here, we used REMD to determine equilibrium populations, rather than the metadynamics. This substitution is tested here.…”

Structure prediction of cyclic peptides by molecular dynamics + machine learning

“…[1][2][3] Notably, most cyclic peptides reported thus far are poorly structured and adopt multiple conformations in solution. [4][5][6][7][8][9][10][11][12][13][14] Critically, the ability of a cyclic peptide to adopt multiple conformations can be essential to its biological properties and functions. For example, the chameleonic structural properties of some cyclic peptides are likely responsible for their high cell membrane permeability.…”

Conformational selection of vasopressin upon V1a receptor binding

“…In particular, nuclear magnetic resonance (NMR) spectroscopy – the major structure elucidation technique for non-crystallizable substrates in solution – is limited by the absence of long-range distance information (e.g., by nuclear Overhauser effects; NOE [42] ). Consequently, combinations of NMR and computational techniques [38] , [43] have become increasing popular to reveal the complex dynamics of VP and related SARs. In this context, we capitalized in this work on an integrative approach combining in-silico modelling of the VP-ligand-receptor complexes and NMR-based structure validation.…”