A computational study of cyclic peptides with vibrational circular dichroism

Abstract

<p>Cyclic peptides are a class of molecules that has shown antimicrobial potential. These are complex compounds to investigate with their large conformational space and multiple chiral centers. A technique that can be used to investigate both conformational preferences and absolute configuration (AC) is vibrational circular dichroism (VCD). To extract information from the experimental VCD spectra a comparison with calculated spectra is often needed and this is the focus of this thesis: the calculation of VCD spectra. <p>The VCD spectra are very sensitive to small structural changes, and to accurately calculate the spectra, all important conformers need to be identified. The first part of this thesis has been to establish a reliable computational protocol using meta-dynamics to sample the conformational space and <i>ab initio</i> methods to calculate the spectra for cyclic peptides. <p>Using our protocol, we have investigated if VCD alone can determine the AC of cyclic tetra- and hexapeptides. We show that it is possible to determine the AC of the cyclic peptides with two chiral centers while for the peptides with three and four chiral centers, VCD is at best able to reduce the number of possible ACs and further investigation with other techniques is needed. <p>Further, we investigated four cyclic hexapeptides with antimicrobial potential. These peptides, in contrast to the ones used for validating the protocol, consist of several amino acids with long and positively charged side chains. For these peptides, a molecular dynamics based approach provided VCD spectra in better agreement with experiment than our protocol. Reasons for this may be the lack of atomistic detail in the solvent model used during the conformational search and insufficient description of dispersion interactions during the meta-dynamics simulation.