20572
J. Phys. Chem. B 2005, 109, 20572-20578
Can Proteins and Crystals Self-Catalyze Methyl Rotations? Jerome Baudry*,† and Jeremy C. Smith‡ School of Chemical Sciences, UniVersity of Illinois at Urbana-Champaign, Urbana, Illinois 61801, and Computational Molecular Biophysics, IWR, UniVersity of Heidelberg, Heidelberg, Germany ReceiVed: June 9, 2005; In Final Form: August 25, 2005
The χ (CR-Cβ) torsional barrier in the dipeptide alanine (N-methyl-L-alanyl-N-methylamide) crystal was investigated using ab initio calculations at various levels of theory, molecular mechanics, and molecular dynamics. For one of the two molecules in the asymmetric unit the calculations suggest that rotation around the χ dihedral angle is catalyzed by the crystal environment, reducing by up to ∼2kT the torsional barrier in the crystal with respect to that in the gas phase. This catalytic effect is present at both low and room temperature and originates from a van der Waals destabilization of the minima in the methyl dihedral potential coming from the nonbonded environment of the side chain. Screening of a subset of the Protein Data Bank with a pharmacophore model reproducing the crystal environment around this side chain methyl identified a protein containing an alanine residue with an environment similar to that in the crystal. Calculations indicate that this χ torsional barrier is also reduced in the protein at low temperature but not at room temperature. This suggests that environment-catalyzed rotation of methyl groups can occur both in the solid phase and in native biological structures, though this effect might be temperature-dependent. The relevance of this catalytic effect is discussed in terms of its natural occurrence and its possible contribution to the low-frequency vibrational modes of molecules.
Introduction Small peptides or peptide-like organic molecules, such as the alanine dipeptide, N-methylacetamide (NMA), and acetanilide, are well-suited for the study of the effects of nonbonded interactions on the structure, dynamics, and thermodynamics of protein constituents and are amenable to both experimental and high-level theoretical studies. Of particular interest are lowfrequency conformational dynamics in biomolecular crystals, as they involve collective movements of atoms that are strongly influenced by nonbonded interactions. In previous work, methyl group energetics and dynamics were investigated using quantum chemical and empirical force field calculations and inelastic neutron scattering experiments. A cooperative effect of hydrogen bonding to the peptide groups on the torsional barrier around the φ and ψ dihedrals of NMA was found in ab initio calculations1 and in molecular mechanics calculations.2 The dynamics of the terminal (φ and ψ) methyl groups was further investigated in acetanilide3 and the alanine dipeptide4,5 by comparing empirical force field calculations of the density of states with experimental inelastic neutron scattering spectra. These studies showed that the low-frequency (
