Conformational Distributions of N‐Acetyl‐L‐cysteine in Aqueous Solutions: A Combined Implicit and Explicit Solvation Treatment of VA and VCD Spectra

Abstract

The conformational distributions of N-acetyl-L-cysteine (NALC) in aqueous solutions at several representative pH values are investigated using vibrational absorption (VA), UV/Vis, and vibrational circular dichroism (VCD) spectroscopy, together with DFT and molecular dynamics (MD) simulations. The experimental VA and UV/Vis spectra of NALC in water are obtained under strongly acid, neutral, and strongly basic conditions, as well as the VCD spectrum at pH 7 in D(2)O. Extensive searches are carried out to locate the most stable conformers of the protonated, neutral, deprotonated, and doubly deprotonated NALC species at the B3LYP/6-311++G(d,p) level. The inclusion of the polarizable continuum model (PCM) modifies the geometries and the relative stabilities of the conformers noticeably. The simulated PCM VA spectra show significantly better agreement with the experimental data than the gas-phase ones, thus allowing assignment of the conformational distributions and dominant species under each experimental condition. To further properly account for the discrepancies noted between the experimental and simulated VCD spectra, PCM and the explicit solvent model are utilized. MD simulations are used to aid the modelling of the NALC-(water)(N) clusters. The geometry optimization, harmonic frequency calculations, and VA and VCD intensities are computed for the NALC-(water)(3,4) clusters at the B3LYP/6-311++G(d,p) level without and with the PCM. The inclusion of both explicit and implicit solvation models at the same time provides a decisively better agreement between theory and experiment and therefore conclusive information about the conformational distributions of NALC in water and hydrogen-bonding interactions between NALC and water molecules.