Vibrational properties of solutions are frequently simulated with clusters of a solute and a few solvent molecules obtained during molecular dynamics (MD) simulations. The raw cluster geometries, however, often provide unrealistic vibrational band broadening, for both ab initio and empirical force fields. In this work, partial optimization in normal-mode coordinates is used on empirical basis to reduce the broadening. The origin of the error is discussed on a simplified two-dimensional system, which indicates that the problem is caused by the anharmonic MD potential, mode coupling, and neglect of quantum effects. Then the procedure of partial geometry optimization on Raman and Raman optical activity (ROA) spectra is applied and analyzed for the solvated lactamide molecule. Comparison to experiment demonstrates that the normal-mode partial optimization technique with a suitable frequency limit can significantly reduce the broadening error. For lactamide, experimental and simulated vibrational bandwidths are compared; the most realistic theoretical spectra are obtained for partially optimized clusters with the vibrational wavenumber cutoff of about 200 cm(-1).
A model peptide, cyclo-(Phe-d-Pro-Gly-Arg-Gly-Asp), with a distinct folded structure containing short beta-hairpin and beta-sheet patterns was studied by Raman and Raman optical activity (ROA) spectroscopies. Unlike for previously analyzed vibrational circular dichroism of the same compound (Chirality 2008, 20, 1104), the Raman spectrum is dominated by side chain contributions and is more sensitive to their geometry fluctuations. The spectra and molecular motion were analyzed with the aid of the density functional theory simulations combined with molecular dynamics (MD). The side chain geometry fluctuations were found to significantly contribute to the broadening of the spectral bands, while dynamics of the backbone is rather restricted. According to our MD results, the side chains do not move freely but largely oscillate around preferred conformations. Averaging of computed spectra for many structures derived from the MD trajectories provided better spectral profiles than did a fixed geometry. The Raman and ROA scattering is dominated by the more polarizable phenylalanine and proline groups, as could be verified both by the computations and by comparison to experiments with a model Phe-d-Pro dipeptide. Computational analyses suggest that the ROA spectrum mostly senses local side chain conformation, whereas a vibrational coupling between different side chains contributes less. The coupling is mostly mediated by the peptide backbone and is restricted to specific vibrational region. The ROA spectroscopic technique thus provides important local structural information that needs, however, to be extracted by multiscale (QM/MM) simulation techniques.
Increasing precision of contemporary computational methods makes spectroscopies such as vibrational (VCD) and electronic (ECD) circular dichroism attractive for determination of absolute configurations (AC) of organic compounds. This is, however, difficult for polar, flexible molecules with multiple chiral centers. Typically, a combination of several methods provides the best picture of molecular behavior. As a test case, all possible stereoisomers with known AC (RS, SR, SS, and RR) of the cyclic dipeptide cyclo(Arg-Trp) (CAT) were synthesized, and the performances of the ECD, infrared (IR), VCD, Raman, Raman optical activity (ROA), and nuclear magnetic resonance (NMR) techniques for AC determination were investigated. The spectra were interpreted with the aid of density functional theory (DFT) calculations. Folded geometries stabilized by van der Waals and electrostatic interactions between the diketopiperazine (DKP) ring and the indole group are predicted to be preferred for CAT, with more pronounced folding due to Arg-Trp stacking in the case of SS/RR-CAT. The RS/SR isomers prefer a twist-boat puckering of the DKP ring, which is relatively independent of the orientation of the side chains. Calculated conformer-averaged VCD and ECD spectra explain most of the experimentally observed bands and allow for AC determination of the tryptophan side-chain, whereas the stereochemical configuration of the arginine side-chain is visible only in VCD. NMR studies provide characteristic long-range (2)J(C,H) and (3)J(C,H) coupling constants, and nuclear Overhauser effect (NOE) correlations, which in combination with either ECD or VCD also allow for complete AC determination of CAT.
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