1. Simulation study of the structure and dynamics of the Alzheimer's amyloid peptide congener in solution
F Massi, J W Peng, J P Lee, J E Straub Biophys J. 2001 Jan;80(1):31-44. doi: 10.1016/S0006-3495(01)75993-0.
The amyloid Abeta(10-35)-NH2 peptide is simulated in an aqueous environment on the nanosecond time scale. One focus of the study is on the validation of the computational model through a direct comparison of simulated statistical averages with experimental observations of the peptide's structure and dynamics. These measures include (1) nuclear magnetic resonance spectroscopy-derived amide bond order parameters and temperature-dependent H(alpha) proton chemical shifts, (2) the peptide's radius of gyration and end-to-end distance, (3) the rates of peptide self-diffusion in water, and (4) the peptide's hydrodynamic radius as measured by quasielastic light scattering experiments. A second focus of the study is the identification of key intrapeptide interactions that stabilize the central structural motif of the peptide. Particular attention is paid to the structure and fluctuation of the central LVFFA hydrophobic cluster (17-21) region and the VGSN turn (24-27) region. There is a strong correlation between preservation of the structure of these elements and interactions between the cluster and turn regions in imposing structure on the peptide monomer. The specific role of these interactions in relation to proposed mechanisms of amyloidosis is discussed.
2. Structural and dynamical analysis of the hydration of the Alzheimer's beta-amyloid peptide
Francesca Massi, John E Straub J Comput Chem. 2003 Jan 30;24(2):143-53. doi: 10.1002/jcc.10101.
An analysis of the water molecules in the first solvation shell obtained from the molecular dynamics simulation of the amyloid beta(10-35)NH2 peptide and the amyloid beta(10-35)NH2E22Q "Dutch" mutant peptide is presented. The structure, energetics, and dynamics of water in the hydration shell have been investigated using a variety of measures, including the hydrogen bond network, the water residence times for all the peptide residues, the diffusion constant, experimentally determined HN amide proton exchange, and the transition probabilities for water to move from one residue to another or into the bulk. The results of the study indicate that: (1) the water molecules at the peptide-solvent interface are organized in an ordered structure similar for the two peptide systems but different from that of the bulk, (2) the peptide structure inhibits diffusion perpendicular to the peptide surface by a factor of 3 to 5 relative to diffusion parallel to the peptide surface, which is comparable to diffusion of bulk water, (3) water in the first solvation shell shows dynamical relaxation on fast (1-2 ps) and slow (10-40 ps) time scales, (4) a novel solvent relaxation master equation is shown to capture the details of the fast relaxation of water in the peptide's first solvation shell, (5) the interaction between the peptide and the solvent is stronger in the wild type than in the E22Q mutant peptide, in agreement with earlier results obtained from computer simulations [Massi, F.; Straub, J. E. Biophys J 2001, 81, 697] correlated with the observed enhanced activity of the E22Q mutant peptide.