ABSTRACT The amyloid peptide congener Ap(10-35)-NH, is simulated in an aqueous environment in both the wild type (WT) and E22Q "Dutch" mutant forms. The origin of the noted increase in deposition activity resulting from the Dutch mutation is investigated. Multiple nanosecond time scale molecular dynamics trajectories were performed and analyzed using a variety of measures of the peptide's average structure, hydration, conformational fluctuations, and dynamics. The results of the study support the conclusions that 1) the E22Q mutant and WT peptide are both stable in "collapsed coil" conformations consistent with the WT structure of Zhang et al. (2000, J. Struct. Biol. 130:130-141); 2) the E22Q peptide is more flexible in solution, supporting early claims that its equilibrium structural fluctuations are larger than those of the WT peptide; and 3) the local E22Q mutation leads to a change in the first solvation layer in the region of the peptide's "hydrophobic patch," resulting in a more hydrophobic solvation of the mutant peptide. The simulation results support the view that the noted increase in activity due to the Dutch mutation results from an enhancement of the desolvation process that is an essential step in the aggregation of the peptide.
SUMMARY AND CONCLUSIONS
The results of our multiple-nanosecond time scale molecular dynamics trajectories of the solvated AP peptide congener in its WT and E22Q mutant forms support a number of conclusions related to the structure, fluctuations, dynamics, and hydration of the peptide.
1. The E22Q mutant and WT peptide are both stable in cc conformations consistent with the WT structure of Lee and coworkers (Zhang et al., 2000). The structure of the central hydrophobic core is preserved throughout the entire simulation for both systems.
2. In solution, the E22Q peptide is more flexible than the WT, supporting an early hypothesis that the equilibrium structural fluctuations of the E22Q mutant peptide were larger than those of the WT peptide (Zhang et al., 1998). The E22Q mutant peptide presents a wider distribution of the end-to-end distances than does the WT peptide. The fluctuations of the theta and psi angles of the residues in the 22-27 region are larger in the E22Q mutant than in the WT peptide. The RMS fluctuations of atoms of the E22Q peptide are larger than those of the WT for all the aminoacids in the 17-26 region.
3. The values of the S2 order parameter are consistently smaller in the Dutch mutant than in the WT peptide in the region between residue 21 and residue 26, which indicates that the motion of the NH amide bond is less restricted in the Dutch mutant than in the WT peptide. The absence of hydrogen bonds between the LVFFA and the VGSN regions in the E22Q mutant, which are present in the WT peptide, is correlated with the higher degree of flexibility of the structure of the mutant peptide around residue 22.
4. A comparison of the solvent-exposed surface area of the two peptides shows that the E22Q mutant peptide has a greater hydrophobic surface area exposed to the solvent. The mutant peptide also presents a larger radius of gyration than does the WT peptide. The local E22Q mutation leads to a local perturbation of the peptide hydration and the structure of the first solvation layer in the region of residue 22.
5. The water-water interaction energy for the waters of the first solvation shell of the LVFFA hydrophobic patch residues is significantly more favorable (more negative) in the mutant peptide. This is correlated with a less favorable (less negative) water-peptide interaction. Both observations are consistent with the formation of a more hydrophobic solvation shell over the hydrophobic patch of the E22Q mutant peptide. This difference should result in a small energetic cost of desolvation of the Dutch mutant peptide in the aggregation process relative to the WT peptide. These observations suggest that the Dutch mutant peptide may have a lower barrier and larger enthalpic driving force to desolvation and aggregation than does the WT peptide, in agreement with the noted increased activity of the Dutch mutant peptide.
We thank the referees and Troy Whitfield for helpful comments on an earlier version of this manuscript. J.E.S. gratefully acknowledges the generous support of the National Institutes of Health (1801 NS41356-01), National Science Foundation (CHE-9975494) and the Petroleum Research Fund of the American Chemical Society (34348-AC6). We also acknowledge the Center for Computational Science at Boston University that provided essential computational resources.
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[Author Affiliation]
Francesca Massi and John E. Straub
Department of Chemistry, Boston University, Boston, Massachusetts 02215 USA
[Author Affiliation]
Received for publication 22 December 2000 and in final form 18 April 2001.
[Author Affiliation]
Address reprint requests to John E. Straub, Boston University, Dept. of Chemistry, 590 Commonwealth Ave., Boston, MA 02215. Tel.: 617-3536816; Fax: 617-353-6466; E-mail: straub@bu.edu.
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