A polarizable QM/MM approach to the molecular dynamics of amide groups solvated in water

Abstract

The infrared (IR) spectra of polypeptides are dominated by the so-called amide bands. Because they originate from the strongly polar and polarizable amide groups (AGs) making up the backbone, their spectral positions sensitively depend on the local electric fields. Aiming at accurate computations of these IR spectra by molecular dynamics (MD) simulations, which derive atomic forces from a hybrid quantum and molecular mechanics (QM/MM) Hamiltonian, here we consider the effects of solvation in bulk liquid water on the amide bands of the AG model compound N-methyl-acetamide (NMA). As QM approach to NMA we choose grid-based density functional theory (DFT). For the surrounding MM water, we develop, largely based on computations, a polarizable molecular mechanics (PMM) model potential called GP6P, which features six Gaussian electrostatic sources (one induced dipole, five static partial charge distributions) and, therefore, avoids spurious distortions of the DFT electron density in hybrid DFT/PMM simulations. Bulk liquid GP6P is shown to have favorable properties at the thermodynamic conditions of the parameterization and beyond. Lennard-Jones (LJ) parameters of the DFT fragment NMA are optimized by comparing radial distribution functions in the surrounding GP6P liquid with reference data obtained from a "first-principles" DFT-MD simulation. Finally, IR spectra of NMA in GP6P water are calculated from extended DFT/PMM-MD trajectories, in which the NMA is treated by three different DFT functionals (BP, BLYP, B3LYP). Method-specific frequency scaling factors are derived from DFT-MD simulations of isolated NMA. The DFT/PMM-MD simulations with GP6P and with the optimized LJ parameters then excellently predict the effects of aqueous solvation and deuteration observed in the IR spectra of NMA. As a result, the methods required to accurately compute such spectra by DFT/PMM-MD also for larger peptides in aqueous solution are now at hand.

An efficient water force field calibrated against intermolecular THz and Raman spectra

“…All density functional theory (DFT) calculations were performed with the Gaussian plane wave formalism implemented in the CP2K program. 65,66 As in Tavan's work, 44,50 the exchange-and correlation functional of Perdew, Burke, and Ernzerhof (PBE) was used. 67 The electron density was expanded in augmented quadruple zeta basis sets with three sets of polarization functions for both H and O atoms.…”

“…14 in order to simulate a Raman spectrum, which is related to the autocorrelation function of the polarizability, the water model needs to be polarizable. A multitude of polarizable water force fields have been developed, treating polarizability in many different ways, i.e., Drude oscillator models, [22][23][24][25][26][27] first principle water models, [28][29][30] models including three-body interactions explicitly, 31,32 fluctuating charge models, 33,34 and models with an inducible dipole moment [35][36][37][38][39][40][41][42][43][44] or higher electrostatic moments. 38,45,46 Beyond that-and that is no longer standard for most water models-the electrostatic properties need to be fine-tuned to reproduce accurate transition dipoles as well as transition polarizabilities so that the relative intensities in the THz and Raman spectra agree with experiment.…”

“…A Gaussian inducible dipole has the same effect, 48,49 which is the basis of a series of water models recently introduced by Tavan and co-workers. 44,50 As a cornerstone in the design of these models, the dipole moment and polarizability of an isolated water molecule were set to the experimental gas phase value. This design philosophy ensures that the models are transferable to different environments and, as a side aspect, also correctly account for a Raman interaction with an external laser field.…”

Monitoring transient events in infrared spectra using local mode analysis

“…A combination of theoretical quantum mechanics (QM) (or quantum mechanics/molecular mechanics [QM/MM] for larger systems) and experimental approaches in vibrational spectroscopy is well suited to connect atomic structural properties with spectral features. This combination is well‐established and has been demonstrated in many applications …”

“…This combination is well-established and has been demonstrated in many applications. [3][4][5][6][7][8][9][10][11][12] Using time-resolved Fourier transformed infrared (FTIR) difference spectroscopy, it is possible to study the structural transitions and reaction steps in proteins in short time periods. This already enabled a deeper understanding of various reaction mechanisms, such as the light-driven proton pump bacteriorhodopsin 13 or the GTPase mechanism of the Ras protein.…”