Simulation of molecular crowding effects on an Alzheimer's beta-amyloid peptide

Fibril formation by the Alzheimer's beta-amyloid (Abeta) peptide in brain tissue is integral to the Alzheimer's disease pathology. Understanding the conformational properties and the mechanisms triggering aggregation of the Abeta peptides, at an atomic level of detail, is of crucial importance for the design of effective therapeutic agents against this disease. In this work, the conformational transitions and dynamic properties of an amyloidogenic peptide fragment (Abeta10-35) were studied by molecular dynamics simulations in systems modeling infinite dilution and the presence of macromolecular crowding agents (CA). The model system consists of the peptide described with an atomistic force field, the CA represented by inert, quasi-hard spheres and a continuum solvent model. This combined model allowed the simulations to be extended to 100 ns each. Simulations were carried out starting from a completely extended structure, a beta-strand structure, and four nuclear magnetic resonance structures in dilute aqueous solution. For all structures, two additional simulations were performed that included the inert CA in the solution and occupied approx 30 and 40% of the volume, respectively. For two of the nuclear magnetic resonance structures, additional simulations were carried out with 35% volume fraction of CA to further examine the diffusive behavior of the peptide. The peptide adopted a collapsed coil conformation in all simulations. The results of the simulations in dilute solution showed reasonable qualitative agreement with experimental and other simulation results, whereas the presence of volume excluding agents resulted in some distinct changes in properties (e.g., an increase in the appearance of transient beta-structure or decreases in diffusivity with increasing CA concentration). At the same time, internal motion such as order parameters or atomic root mean square fluctuations showed less systematic responses to volume exclusion.