Premium
Structure Determination of a Flexible Cyclic Peptide Based on NMR and MD Simulation 3 J ‐Coupling
Author(s) -
Gattin Zrinka,
Zaugg Judith,
van Gunsteren Wilfred F.
Publication year - 2010
Publication title -
chemphyschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.016
H-Index - 140
eISSN - 1439-7641
pISSN - 1439-4235
DOI - 10.1002/cphc.200900501
Subject(s) - chemistry , tetrapeptide , residual dipolar coupling , molecular dynamics , coupling constant , coupling (piping) , j coupling , dipole , multiplicity (mathematics) , magnetic dipole–dipole interaction , molecule , computational chemistry , statistical physics , molecular physics , nuclear magnetic resonance spectroscopy , peptide , physics , stereochemistry , materials science , quantum mechanics , mathematics , mathematical analysis , biochemistry , organic chemistry , metallurgy
Abstract Molecular dynamics (MD) simulations, in which experimental values such as nuclear Overhauser effects (NOEs), dipolar couplings, 3 J ‐coupling constants or crystallographic structure factors are used to bias the values of specific molecular properties towards experimental ones, are often carried out to study the structure refinement of peptides and proteins. However, 3 J ‐coupling constants are usually not employed because of the multiplicity of torsional angle values (φ) corresponding to each 3 J ‐coupling constant value. Here, we apply the method of adaptively enforced restraining using a local‐elevation (LE) biasing potential energy function in which a memory function penalizes conformations in case both the average < 3 J > and the current 3 J ‐values deviate from the experimental target value. Then, the molecule is forced to sample other parts of the conformational space, thereby being able to cross high energy barriers and to bring the simulated average < 3 J > close to the measured < 3 J > value. Herein, we show the applicability of this method in structure refinement of a cyclo‐β‐tetrapeptide by enforcing the 3 J ‐value restraining with LE on twelve backbone torsional angles. The resulting structural ensemble satisfies the experimental 3 J ‐coupling data better than the NMR model structure derived using conventional single‐structure refinement based on these data. Thus, application of local‐elevation search MD simulation in combination with biasing towards 3 J ‐coupling makes it possible to use 3 J ‐couplings quantitatively in structure determination of peptides.