Comparison of Polarizable Continuum & Quantum Mechanics/Molecular Mechanics Models with Series of Tripeptides (AXA)

Abstract

In biomolecule simulations solvation is a key factor in representing experimental conditions. Recent studies use models like Quantum Mechanics and Molecular Mechanics (QM/MM) and Polarizable Continuum Model (PCM) to attempt to simulate solvent effects on spectra. For proteins and peptides vibrational analyses primarily focuses on amide I (due to its isolation and strong dipole moment) to determine information about the secondary structure (α-helix, β-sheet, PPII). In this study we compare the QM/MM and PCM models with a focus on amide I at ∼1650 cm−1 (mainly amide C=O stretch) and also extended to lower energy amide II (∼ 1550 cm−1) in order to gain insight into the effectiveness of either method. We modeled a series of tripeptides (AXA: where X=A, E, S, W) and capped at N- and C- termini to yield Ac-Ala-Xxx-Ala-NH2. For QM/MM studies, we first sampled the conformations with an explicit solvent using Charmm 36 force field. The simulations were executed for 20 ns using periodic boundary conditions, with constant pressure and temperature (NPT ensemble) at 300 K and 1 atm. We then obtained the most preferable conformation (which is PPII-like) and extracted the geometry for both PCM and QM/MM level calculation to generate IR and VCD spectra. Furthermore, PCM Model was computed with an ideal PPII-like conformation (−78,149,180) to compare with preferable conformation obtained from MD simulation. The geometry was constrained (in terms of φ, ψ torsional angles) and prepared for optimization. With PCM model we use an implicit solvent while in QM/MM we use an explicit solvation shell of 10A. All calculations were fully optimized across all coordinates except (φ, ψ, ω, which were fixed) at the DFT BPW91/6-31G∗∗ level of theory. By observing amide I and amide II, accurate inferences about the different types of theory were made.