Molecular dynamics simulation of configurational ensembles compatible with experimental FRET efficiency data through a restraint on instantaneous FRET efficiencies

• Published in: Journal of computational chemistry 2014-12, Vol.35 (32), p.2319-2332
• Main Authors: Reif, Maria M., Oostenbrink, Chris
• Format: Article
• Language: English
• Subjects: Cluster analysis; experimental restraints; Fluorescence Resonance Energy Transfer; Förster resonance energy transfer; mastoparans; molecular dynamics; Molecular Dynamics Simulation; Molecules; peptide conformation; Peptides; Simulation
• ISSN: 0192-8651; 1096-987X
• DOI: 10.1002/jcc.23756

Förster resonance energy transfer (FRET) measurements are widely used to investigate (bio)molecular interactions or/and association. FRET efficiencies, the primary data obtained from this method, give, in combination with the common assumption of isotropic chromophore orientation, detailed insight into the lengthscale of molecular phenomena. This study illustrates the application of a FRET efficiency restraint during classical atomistic molecular dynamics simulations of a mutant mastoparan X peptide in either water or 7 M aqueous urea. The restraint forces acting on the donor and acceptor chromophores ensure that the sampled peptide configurational ensemble satisfies the experimental primary data by modifying interchromophore separation and chromophore transition dipole moment orientations. By means of a conformational cluster analysis, it is seen that indeed different configurational ensembles may be sampled without and with application of the restraint. In particular, while the FRET efficiency and interchromophore distances monitored in an unrestrained simulation may differ from the experimentally‐determined values, they can be brought in agreement with experimental data through usage of the FRET efficiency restraining potential. Furthermore, the present results suggest that the assumption of isotropic chromophore orientation is not always justified. The FRET efficiency restraint allows the generation of configurational ensembles that may not be accessible with unrestrained simulations, and thereby supports a meaningful interpretation of experimental FRET results in terms of the underlying molecular degrees of freedom. Thus, it offers an additional tool to connect the realms of computer and wet‐lab experimentation. © 2014 Wiley Periodicals, Inc. This work describes how a special restraint potential energy term can be used in molecular dynamics simulations of a system undergoing Förster resonance energy transfer (FRET) to bring the simulated FRET efficiency in agreement with the FRET efficiency measured in experiment. The methodology thus allows the generation of configurational ensembles that may not be accessible with unrestrained simulations, and thereby supports a meaningful interpretation of experimental FRET results in terms of the underlying molecular degrees of freedom (interchromophore distances and orientations).