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 are characterized from molecular dynamics 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 1D 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 self-consistent charge density functional tight-binding (SCC-DFTB) simulations, compared with 25 cm −1 from experiment. The frequency trajectory required for the frequency fluctuation correlation function (FFCF) is determined from individual normal mode (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 Δ 0 2 from simulations using MTP and analysis based on FNM are all consistent with experiments for (Ala) 3 . Contrary to this, 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 Δ 0 2 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 and α R . This agrees with and confirms recently reported Bayesian-refined populations based on 1D infrared experiments. FNM analysis together with a MTP representation provides a meaningful model to correctly describe the dynamics of hydrated trialanine.

Quantitative molecular simulations

“…Interestingly, the final ensemble generated from such an approach was similar to the Ramachandran maps from explicit MD simulations using a multipolar representation which also correctly described the IR spectroscopy. 121 …”

Quantitative Molecular Simulations

“…109,111 Alternatively, MD simulations with physics-based and improved force fields can be used to determine the underlying structural features by comparing computed and experimentally measured IR spectra. 112,113 N-methyl acetamide (NMA) is a topical example for which substantial experimental and from using a standard force field. The simulation results using a multipolar representation favour a larger value for the decay times which is more consistent with the experimental findings.…”

“…A slightly larger and equally well-studied system is trialanine (Ala 3 ). 112,113,[116][117][118][119][120][121][122][123][124][125] Most experiments were carried out under conditions that prefer the cationic species and agree that the conformational ensemble is dominated by the poly-proline II (ppII) structure, often together with some population of the β−sheet conformation and rare sampling of a right-handed α−helical structure. From 1-d and 2-d IR experiments in the amide-I region a notable study used spectroscopic data to refine the underlying conformational ensemble generated from MD simulations.…”

“…Interestingly, the final ensemble generated from such an approach was similar to the Ramachandran maps from explicit MD simulations using a multipolar representation which also correctly described the IR spectroscopy. 113 IR spectroscopy can also be used to follow protein assembly and disassembly. Insulin binds to the insulin receptor in its monomeric form but is stored in the body as a zinc-bound hexamer each of which consists of three homodimers.…”

Computational Vibrational Spectroscopy

“…47 This was successfully done using reproducing kernel-based representations for the amide-I mode in insulin and trialanine or for azide attached to all alanine residues in Lysozyme. [48][49][50] This provides a positionally sensitive probe of the protein dynamics to follow protein assembly or protein-ligand interactions.…”