Molecular Dynamics Simulations of Conformational Conversions in Transformer Proteins.

A relatively recently discovered class of proteins known as transformer proteins undergo large-scale conformational conversions that change their supersecondary structure. These structural transformations lead to different configurations that perform different functions. We describe computational methods using molecular dynamics simulations that allow the determination of the specific amino acids that facilitate the conformational transformations. These investigations provide guidance on the location and type of amino acid mutations that can either enhance or inhibit the structural transitions that allow transformer proteins to perform multiple functions.

Cooperative structural transitions in amyloid-like aggregation.

Amyloid fibril aggregation is associated with several horrific diseases such as Alzheimer's, Creutzfeld-Jacob, diabetes, Parkinson's, and others. Although proteins that undergo aggregation vary widely in their primary structure, they all produce a cross-ß motif with the proteins in ß-strand conformations perpendicular to the fibril axis. The process of amyloid aggregation involves forming myriad different metastable intermediate aggregates. To better understand the molecular basis of the protein structural transitions and aggregation, we report on molecular dynamics (MD) computational studies on the formation of amyloid protofibrillar structures in the small model protein ccß, which undergoes many of the structural transitions of the larger, naturally occurring amyloid forming proteins. Two different structural transition processes involving hydrogen bonds are observed for aggregation into fibrils: the breaking of intrachain hydrogen bonds to allow ß-hairpin proteins to straighten, and the subsequent formation of interchain H-bonds during aggregation into amyloid fibrils. For our MD simulations, we found that the temperature dependence of these two different structural transition processes results in the existence of a temperature window that the ccß protein experiences during the process of forming protofibrillar structures. This temperature dependence allows us to investigate the dynamics on a molecular level. We report on the thermodynamics and cooperativity of the transformations. The structural transitions that occurred in a specific temperature window for ccß in our investigations may also occur in other amyloid forming proteins but with biochemical parameters controlling the dynamics rather than temperature.

Kinetics of peptide secondary structure conversion during amyloid ß-protein fibrillogenesis.

Amyloid fibrils are a common component in many debilitating human neurological diseases such as Alzheimer's (AD), Parkinson's, and Creutzfeldt-Jakob, and in animal diseases such as BSE. The role of fibrillar Αß proteins in AD has stimulated interest in the kinetics of Αß fibril formation. Kinetic models that include reaction pathways and rate parameters for the various stages of the process can be helpful towards understanding the dynamics on a molecular level. Based upon experimental data, we have developed a mathematical model for the reaction pathways and determined rate parameters for peptide secondary structural conversion and aggregation during the entire fibrillogenesis process from random coil to mature fibrils, including the molecular species that accelerate the conversions. The model and the rate parameters include different molecular structural stages in the nucleation and polymerization processes and the numerical solutions yield graphs of concentrations of different molecular species versus time that are in close agreement with experimental results. The model also allows for the calculation of the time-dependent increase in aggregate size. The calculated results agree well with experimental results, and allow differences in experimental conditions to be included in the calculations. The specific steps of the model and the rate constants that are determined by fitting to experimental data provide insight on the molecular species involved in the fibril formation process.