Multiple Loop Conformations of Peptides Predicted by Molecular Dynamics Simulations Are Compatible with Nuclear Magnetic Resonance

Abstract

The affinity and selectivity of protein-protein interactions can be fine-tuned by varying the size, flexibility, and amino acid composition of involved surface loops. As a model for such surface loops, we study the conformational landscape of an octapeptide, whose flexibility is chemically steered by a covalent ring closure integrating an azobenzene dye into and by a disulfide bridge additionally constraining the peptide backbone. Because the covalently integrated azobenzene dyes can be switched by light between a bent cis state and an elongated trans state, six cyclic peptide models of strongly different flexibilities are obtained. The conformational states of these peptide models are sampled by NMR and by unconstrained molecular dynamics (MD) simulations. Prototypical conformations and the free-energy landscapes in the high-dimensional space spanned by the phi/psi angles at the peptide backbone are obtained by clustering techniques from the MD trajectories. Multiple open-loop conformations are shown to be predicted by MD particularly in the very flexible cases and are shown to comply with the NMR data despite the fact that such open-loop conformations are missing in the refined NMR structures.

Photoinduced Conformational Dynamics of a Photoswitchable Peptide: A Nonequilibrium Molecular Dynamics Simulation Study

“…We were able to reproduce the NMR data, and also confirmed the general picture drawn by Renner et al (11) that the trans-isomer of bcAMPB exhibits a well-defined structure, whereas the cisisomer represents a conformational heterogeneous system comprising an ensemble of structures. Similar results were obtained by Carstens et al (25) employing high temperature simulations. Second, one wants to describe the laser-induced conformational dynamics of biomolecules, starting from the experimentally achieved nonequilibrium preparation of the system (17,(26)(27)(28)(29)(30)(31).…”

Azobenzene as Conformational Switch in Model Peptides

“…Theorists have taken the challenge, at least for a few of these peptides, and the comparison of experimental and predicted structures (or raw distance data) has revealed quite satisfactory performance of the simulation toolsthe major problem seemingly being presented by conformational sampling despite the small size of the system. [38,39] Nota bene, only equilibrium structures are addressed here, whereas the real interest lies in the conformational dynamics that is triggered by isomerization (see below). A conceptually somewhat different approach was taken by Woolley and co-workers.…”

“…[37,[45][46][47][48] Molecular dynamics (MD) simulations of the cis-to trans-azo isomerization of the first APB-peptide showed a surprisingly good agreement with the experiment when energy contained in the peptide (in the MD) was compared to the time-dependent shift of the absorption band (in the experiment). [24,39,45] Therefore, the MD approach seems validated and individual details of the conformational dynamics that are experimentally inaccessible can readily be obtained from MD trajectories. [24,45] In fact, the interpretation given above is substantiated namely by the fact that during the "hot phase", when substantial excess energy is contained in the system, only small rotations of a few bonds accommodate the altered geometry of the light switch.…”

Structural Instability of the Prion Protein upon M205S/R Mutations Revealed by Molecular Dynamics Simulations

“…. ., 100 and the common width s ML of the Gaussians, were optimized by a safely converging algorithm maximizing the likelihood of the density estimates provided by the mixture models p(a js ML ) (32)(33)(34).…”