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.

α-Amino Acids In Water: A Review Of VCD And ROA Spectra

“…the spectra were interpreted by means of B3L-YP/6-311 + + g** calculations and molecular dynamics simulations. As found previously for unsubstituted L-cysteine [137], the energetic order of the protonated, neutral, mono-and doubly-deprotonated N-acetyl-L-cysteine conformers was noticeably changed after the inclusion of the polarisable continuum model. to properly account for the discrepancies noted between the experimental and simulated vCd spectra, the PCm and the explicit solvent model (preceded by the md simulations of N-acetyl-L-cysteine water clusters) were used.…”

“…3. the most satisfactory and more rigorous approach to account for solvation is to perform dynamic simulations, i.e., by employing md or CP-md directly and by simulating the spectra at each time step of the md trajectories ("snapshots" corresponding to, for instance, 10 ns of simulation). this accounts for the inhomogeneous band broadening and Boltzmann averaging of many conformations provided by the conformer distribution [137][138][139][140][141].…”

“…As concluded by Jalkanen et al [144], the hybrid model is the proper approach for further studies of vCd and RoA spectra of amino acids in water. however, very recently, the most promising, yet time-consuming, multiscale approach has been to merge dynamic methods with supermolecular methods and with the PCm model [137][138][139][140][141]. the algorithm contains a few steps: (1) a quantum-chemical exploration of the conformation landscape of the solute molecule (a scan of the potential energy surface, PES) with the PCm model; (2) reoptimisation of the geometry of the complex with a few solvent (water) molecules by quantum methods, or, by a more rigorous approach, finding the geometry of the complexes using the md or CP-md methods; (3) calculation of the spectra for the individual complexes and averaging the final spectrum based on the Boltzmann populations of the complexes, or, by a more rigorous approach, calculation of the spectra for hundreds/thousands of md complexes extracted from snapshots.…”

“…Based on a complex experimental and theoretical study, a cautious and critical assignment of the vibrational bands of L-cysteine in aqueous solution was provided for all four types of vibrational spectra. Let us mention that the vCd, IR, and uv-vis spectra of N-acetyl-L-cysteine, a drug used in detoxifying free radicals, were also measured in aqueous solution (d 2 o) at several ph levels [137]. the spectra were interpreted by means of B3L-YP/6-311 + + g** calculations and molecular dynamics simulations.…”

“…here, the first step is to find the number of solvent molecules hydrogen-bonded to the solute molecule. this can be determined from the analysis of atom-atom radial distribution functions (RdF) or from the generation of solute-solvent clusters as md "snapshots" [66,137]. the second step is the conformational search for the cluster and the simulation of a spectrum.…”