Spectroscopic polarizable force field for amide groups in polypeptides.

The infrared spectra of polypeptides are dominated by the so-called amide bands. These bands originate from the electrostatically coupled vibrations of the strongly polar amide groups (AGs) making up the polypeptide backbone. Because the AGs are highly polarizable, external electric fields can shift the frequencies of the amide normal modes over wide spectral ranges. The sensitivity to external fields and the strong polarity are the reasons why the shapes of the amide bands can code the structure of the polypeptide backbone. Aiming at a decoding of these band shapes, Schultheis et al. (J. Phys. Chem. B 2008, 112, 12217) have recently suggested a polarizable molecular mechanics (PMM) force field for AGs, which employs field dependent force constants and enables the computation of the amide bands from molecular dynamics simulations. Here we extend and refine this first suggestion of such a PMM force field. The extension rests on the choice of suitable internal coordinates for the AGs and on the inclusion of the complete AG Hessian and of its field dependence. The force field parameters are calculated from density functional theory. The improved quality of the resulting PMM descriptions is demonstrated using very simple examples and an outlook is given.

Flexibility does not change the polarizability of water molecules in the liquid.

Molecular mechanics (MM) force fields employed in molecular dynamics simulations of bulk liquid water or of solvated proteins have to appropriately handle the sizable polarizability alpha of the water molecules. Using a hybrid method that combines density functional theory (DFT) for a rigid water molecule with an MM description of the liquid environment, we have recently shown that the induced dipole moment can be accurately calculated by linear response multiplying the experimental gas phase polarizability alpha(exp) with the electric reaction field averaged over the volume of the molecule [B. Schropp and P. Tavan, J. Phys. Chem. B 2008, 112, 6233]. However, water molecules are flexible, and the strong local fields acting in the liquid can change their geometries. These changes of geometry can modify both the dipole moment and the polarizability. Using a DFT/MM approach for a flexible DFT water model, here we show that the corresponding effects are quite small. Moreover, they even happen to cancel. As a result, rigid, transferable, and polarizable MM models automatically include the couplings between the external field in the bulk liquid, the geometry, and the dipole moment of an embedded water molecule.

A polarizable force field for computing the infrared spectra of the polypeptide backbone.

The shapes of the amide bands in the infrared (IR) spectra of proteins and peptides are caused by electrostatically coupled vibrations within the polypeptide backbone and code the structures of these biopolymers. A structural decoding of the amide bands has to resort to simplified models because the huge size of these macromolecules prevents the application of accurate quantum mechanical methods such as density functional theory (DFT). Previous models employed transition-dipole coupling methods that are of limited accuracy. Here we propose a concept for the computation of protein IR spectra, which describes the molecular mechanics (MM) of polypeptide backbones by a polarizable force field of "type II". By extending the concepts of conventional polarizable MM force fields, such a PMM/II approach employs field-dependent parameters not only for the electrostatic signatures of the molecular components but also for the local potentials modeling the stiffness of chemical bonds with respect to elongations, angle deformations, and torsions. Using a PMM/II force field, the IR spectra of the polypeptide backbone can be efficiently calculated from the time dependence of the backbone's dipole moment during a short (e.g., 100 ps) MD simulation by Fourier transformation. PMM/II parameters are derived for harmonic bonding potentials of amide groups in polypeptides from a series of DFT calculations on the model molecule N-methylacetamide (NMA) exposed to homogeneous external electric fields. The amide force constants are shown to vary by as much as 20% for relevant field strengths. As a proof of principle, it is shown that the large solvatochromic effects observed in the IR spectra of NMA upon transfer from the gas phase into aqueous solution are not only excellently reproduced by DFT/MM simulations but are also nicely modeled by the PMM/II approach. The tasks remaining for a proof of practice are specified.

The polarizability of point-polarizable water models: density functional theory/molecular mechanics results.

Molecular dynamics (MD) simulations of bulk liquid water at different thermodynamic conditions or of biomolecules in aqueous solution require a molecular mechanics (MM) force field that accounts for the sizable electronic polarizability alpha of the water molecule. A considerable number of such polarizable water models has been suggested in the past. Most of them agree that one should employ the experimental value alpha(exp) for the electronic polarizability and compute the induced dipole moment micro(i) through linear response from the electric field E at the position r(o) of the oxygen atom. However, several more recent models have suggested somewhat smaller values for alpha. Using a hybrid method that combines density functional theory for a selected water molecule with an MM description of its liquid water environment, here we show that the choice of alpha(exp) is solely correct if the induced dipole moment mui is calculated from the average electric field E within the volume occupied by the given water molecule. Because of considerable field inhomogeneities caused by the structured aqueous environment, the average field E is much smaller than the local spot check E(r(o)). However, as opposed to E(r(o)), the average field E cannot be easily calculated in MM-MD simulations. Therefore, in polarizable MM water models, one should calculate the induced dipole moment micro(i) from E(r(o)) through the reduced polarizability alpha(eff) = 0.68alpha(exp), which then effectively accounts for the inhomogeneities of the electric field within the volume of a water molecule embedded in liquid water.

Structural instability of the prion protein upon M205S/R mutations revealed by molecular dynamics simulations.

The point mutations M205S and M205R have been demonstrated to severely disturb the folding and maturation process of the cellular prion protein (PrP(C)). These disturbances have been interpreted as consequences of mutation-induced structural changes in PrP, which are suggested to involve helix 1 and its attachment to helix 3, because the mutated residue M205 of helix 3 is located at the interface of these two helices. Furthermore, current models of the prion protein scrapie (PrP(Sc)), which is the pathogenic isoform of PrP(C) in prion diseases, imply that helix 1 disappears during refolding of PrP(C) into PrP(Sc). Based on molecular-dynamics simulations of wild-type and mutant PrP(C) in aqueous solution, we show here that the native PrP(C) structure becomes strongly distorted within a few nanoseconds, once the point mutations M205S and M205R have been applied. In the case of M205R, this distortion is characterized by a motion of helix 1 away from the hydrophobic core into the aqueous environment and a subsequent structural decay. Together with experimental evidence on model peptides, this decay suggests that the hydrophobic attachment of helix 1 to helix 3 at M205 is required for its correct folding into its stable native structure.