Multipolar Force Fields for Amide-I Spectroscopy from Conformational Dynamics of the Alanine-Trimer

Abstract

The dynamics and spectroscopy of N-methyl-acetamide (NMA) and trialanine in solution is characterized from molecular dynamics (MD) simulations using different energy functions, including a conventional point charge (PC)-based force field, one based on a multipolar (MTP) representation of the electrostatics, and a semiempirical DFT method. For the 1-d infrared spectra, the frequency splitting between the two amide-I groups is 10 cm −1 from the PC, 13 cm −1 from the MTP, and 47 cm −1 from SCC-DFTB simulations, compared with 25 cm −1 from experiment. The frequency trajectory required for determining the frequency fluctuation correlation function (FFCF) is determined from individual (INM) and full normal mode (FNM) analyses of the amide-I vibrations. The spectroscopy, time-zero magnitude of the FFCF C(t = 0), and the static component ∆ 2 0 from simulations using MTP and analysis based on FNM are all consistent with experiments for (Ala) 3 . Contrary to that, for the analysis excluding mode-mode coupling (INM) the FFCF decays to zero too rapidly and for simulations with a PC-based force field the ∆ 2 0 is too small by a factor of two compared with experiments. Simulations with SCC-DFTB agree better with experiment for these observables than those from PC-based simulations. The conformational ensemble sampled from simulations using PCs is consistent with the literature (including P II , β, α R , and α L ), whereas that covered by the MTP-based simulations is dominated by P II with some contributions from β, α R . This agrees with and confirms recently reported, Bayesian-refined populations based on 1-dimensional infrared experiments. Full normal mode analysis together with a MTP representation provides a meaningful model to correctly describe the dynamics of hydrated trialanine.

Site-Selective Dynamics of Ligand-Free and Ligand-Bound Azidolysozyme

“…For trialanine (Ala) 3 a value of ∆ 0 = 5 cm −1 was reported 52 compared with ∆ 0 = 4.6 cm −1 from MD simulations (0.94 ps −1 vs. 0.86 ps −1 ) with multipolar force fields. 46 Similarly, CN − in water features a nonvanishing tilt angle by τ = 10 ps 53 with ∆ 0 ∼ 0.1 ps −1 ∼ 0.5 cm −1 . 54 To determine in which way the dynamics of residues is affected upon modification of the protein, dynamical cross-correlation maps 55,56 (DCCM) were calculated from the trajectories using the Bio3D package.…”

“…In a very recent work such an approach found a splitting of 13 cm −1 , compared with 25 cm −1 from experiment, for the outer and central -CO labels in cationic trialanine in water. 46 Hence, MD simulations together with instantaneous normal modes are a meaningful approach to determine relative frequency shifts whereas capturing absolute frequencies in such simulations requires slight reparametrization of the underlying force field, e.g. through morphing techniques.…”