Are solvation free energies of homogeneous helical peptides additive?

in Journal of Physical Chemistry B (2005), 109(40), 19000-19007

We investigated the additivity of the solvation free energy of amino acids in homogeneous helices of different length in water and in chloroform. Solvation free energies were computed by ... [more ▼]

We investigated the additivity of the solvation free energy of amino acids in homogeneous helices of different length in water and in chloroform. Solvation free energies were computed by multiconfiguration thermodynamic integration involving extended molecular dynamics simulations and by applying the generalized-born surface area solvation model to static helix geometries. The investigation focused on homogeneous peptides composed of uncharged amino acids, where the backbone atoms are kept fixed in an ideal helical conformation. We found nonlinearity especially for short peptides, which does not allow a simple treatment of the interaction of amino acids with their surroundings. For homogeneous peptides longer than five residues, the results from both methods are in quite good agreement and solvation energies are to a good extent additive. [less ▲]

Alternative binding modes of proline-rich peptides binding to the GYF domain

in Biochemistry (2005), 44(17), 6404-6415

Recognition of proline-rich sequences plays an important role for the assembly of multiprotein complexes during the course of eukaryotic signal transduction and is mediated by a set of protein folds that ... [more ▼]

Recognition of proline-rich sequences plays an important role for the assembly of multiprotein complexes during the course of eukaryotic signal transduction and is mediated by a set of protein folds that share characteristic features. The GYF (glycine-tyrosine-phenylalanine) domain is known as a member of the superfamily of recognition domains for proline-rich sequences. Recent studies on the complexation of the CD2BP2-GYF domain with CD2 peptides showed that the peptide adopts an extended conformation and forms a polyproline type-II helix involving residues Pro4-Pro7 [Freund et al. (2002) EMBO J. 21, 5985-5995]. R/K/GxxPPGxR/K is the key signature for the peptides that bind to the GYF domain [Kofler et at. (2004) J. Biol. Chem. 279, 28292-28297]. In our combined theoretical and experimental study, we show that the peptides adopt a polyproline 11 helical conformation in the unbound form as well as in the complex. From molecular dynamics simulations, we identify a novel binding mode for the G8W mutant and the wild-type peptide (shifted by one proline in register). In contrast, the conformation of the peptide mutant H9M remains close to the experimentally derived wild-type GYF-peptide complex. Possible functional implications of this altered conformation of the bound ligand are discussed in the light of our experimental and theoretical results. [less ▲]

Solvation free energies and transfer free energies for amino acids from hydrophobic solution to water solution from a very simple residue model

in Journal of Physical Chemistry B (2004), 108(18), 5806-5814

Solvation free energies of neutral amino acids in water and in chloroform were computed from extensive molecular dynamics simulations using multiconfiguration thermodynamic integration. The values ... [more ▼]

Solvation free energies of neutral amino acids in water and in chloroform were computed from extensive molecular dynamics simulations using multiconfiguration thermodynamic integration. The values computed for the AMBER force field are in very good agreement with available experimental data (rms differences of 5.1 kJ mol(-1) for the solvation free energies and 6.4 kJ mol(-1) for the transfer free energies of amino acids between water and chloroform) and with existing calculations. We derived an additive residue-scale solvation model formulated as the sum of a nonpolar term that is proportional to the molecular surface area and an electrostatic term (Kirkwood-Onsager model) for the hydration free energy of a dipole in a solvated cavity. This model can surprisingly well describe the solvation free energies in water and chloroform as well as the transfer free energies of amino acids between the two solvents when suitably adapted cavity radii are used. Root-mean-square differences of the predicted values with respect to the values calculated from thermodynamic integration are 1.8, 5.9, and 7.7 kJ mol(-1), respectively. [less ▲]