Molecular Modeling Studies of the Beta Peptide

Alzheimer’s disease is characterized by extracellular amyloid plaques, whose major protein component is the ß-peptide (39-43 residues). It has been suggested that the ß-peptide is directly involved in the pathogenesis of the disease. One current theory is that the ß-peptide is a normal proteolytic product that aggregates to form plaques as a result of abnormal changes in the environment of the brain. In this way, plaque formation may be accelerated so that it competes with normal degradation. Therefore, it is important to study the solution properties of the ß-peptide to better understand the factors preceding amyloid deposition.

Zagorski and co-workers have recently investigated the conformational properties of various ß-peptide fragments under a variety of conditions. They found that the N-terminal portion of the peptide can preferentially adopt random coil, a-helical, or ß structure depending on the temperature and solvent conditions (e.g. pH and trifluoroethanol concentration). The C-terminal region prefers ß conformations and is thought to drive the aggregation of structure responsible for the plaques. But, detailed structural information for the fragments is limited.

We propose to simulate ß-peptide fragments to investigate their conformational properties, the determinants of secondary structure in these fragments, the conformational sensitivity of amino acid mutations, and the effect of external variables (pH, temperature and solvent) on the conformation. The technique of molecular dynamics will be used to simulate the motion of the peptides and solvent molecules. The ß-peptide is a good system for such studies because of the abundance of structural experimental data available to gauge the validity of the simulations. The experimental data do not, however, provide conformational details, dynamical characteristics of these conformations, nor how solvent influences conformational preferences. The goal of these simulation studies is delineate the details of the conformational properties of the ß-peptide and the relevance of these conformations to the steps preceding intermolecular aggregation leading to amyloids.

In addition, peptide assemblies will be investigated to simulate the aggregation process as a model for the early steps in amyloid deposition. The stability of the aggregated peptide assemblies will then be studied as a function of the environmental parameters in an attempt to identify ways to disrupt the complexes. In addition to elucidating the environmental determinants involved in amyloidosis, hopefully these simulations will provide clues that will aid in drug design efforts by identifying particular interactions during the aggregation process or aggregated state that could be drug targets.

Therefore, the simulations should supplement our knowledge in these areas. Hopefully, these investigations will also lead to a better understanding of the factors leading to plaque formation and ways to retard or reverse the process. In addition to the relevance to Alzheimer’s disease, these studies should shed light on very fundamental conformational properties of peptides and peptide assemblies, which will hopefully be relevant to many other areas of biochemistry including prion diseases, hormone action, ligand receptor interactions, antibacterial peptides, membrane fusion, protein degradation and protein folding.