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Azobenzene-based molecular photoswitches are becoming increasingly important for the development of photoresponsive, functional soft-matter material systems. Upon illumination with light, fast interconversion between a more stable trans and a metastable cis configuration can be established resulting in pronounced changes in conformation, dipole moment or hydrophobicity. A rational design of functional photosensitive molecules with embedded azo moieties requires a thorough understanding of isomerization mechanisms and rates, especially the thermally activated relaxation. For small azo derivatives considered in the gas phase or simple solvents, Eyring’s classical transition state theory (TST) approach yields useful predictions for trends in activation energies or corresponding half-life times of the cis isomer. However, TST or improved theories cannot easily be applied when the azo moiety is part of a larger molecular complex or embedded into a heterogeneous environment, where a multitude of possible reaction pathways may exist. In these cases, only the sampling of an ensemble of dynamic reactive trajectories (transition path sampling, TPS) with explicit models of the environment may reveal the nature of the processes involved. In the present work we show how a TPS approach can conveniently be implemented for the phenomenon of relaxation–isomerization of azobenzenes starting with the simple examples of pure azobenzene and a push–pull derivative immersed in a polar (DMSO) and apolar (toluene) solvent. The latter are represented explicitly at a molecular mechanical (MM) and the azo moiety at a quantum mechanical (QM) level. We demonstrate for the push–pull azobenzene that path sampling in combination with the chosen QM/MM scheme produces the expected change in isomerization pathway from inversion to rotation in going from a low to a high permittivity (explicit) solvent model. We discuss the potential of the simulation procedure presented for comparative calculation of reaction rates and an improved understanding of activated states.
The principles of protein-glycan binding are still not well understood on a molecular level. Attempts to link affinity and specificity of glycan recognition to structure suffer from the general lack of model systems for experimental studies and the difficulty to describe the influence of solvent. We have experimentally and computationally addressed energetic contributions of solvent in protein-glycan complex formation in the tailspike protein (TSP) of E. coli bacteriophage HK620. HK620TSP is a 230 kDa native trimer of right-handed, parallel beta-helices that provide extended, rigid binding sites for bacterial cell surface O-antigen polysaccharides. A set of high affinity mutants bound hexa- or pentasaccharide O-antigen fragments with very similar affinities even though hexasaccharides introduce an additional glucose branch into an occluded protein surface cavity. Remarkably different thermodynamic binding signatures were found for different mutants; however, crystal structure analyses indicated that no major oligosaccharide or protein topology changes had occurred upon complex formation. This pointed to a solvent effect. Molecular dynamics simulations using a mobility-based approach revealed an extended network of solvent positions distributed over the entire oligosaccharide binding site. However, free energy calculations showed that a small water network inside the glucose-binding cavity had the most notable influence on the thermodynamic signature. The energy needed to displace water from the glucose binding pocket depended on the amino acid at the entrance, in agreement with the different amounts of enthalpy-entropy compensation found for introducing glucose into the pocket in the different mutants. Studies with small molecule drugs have shown before that a few active water molecules can control protein complex formation. HK620TSP oligosaccharide binding shows that similar fundamental principles also apply for glycans, where a small number of water molecules can dominate the thermodynamic signature in an extended binding site.