Phase diagrams describing fibrillization by polyalanine peptides

Amyloid fibrils are the structural components underlying the intra- and extracellular protein deposits that are associated with a variety of human diseases, including Alzheimer's, Parkinson's, and the prion diseases. In this work, we examine the thermodynamics of fibril formation using our newly-developed off-lattice intermediate-resolution protein model, PRIME. The model is simple enough to allow the treatment of large multichain systems while maintaining a fairly realistic description of protein dynamics when used in conjunction with constant-temperature discontinuous molecular dynamics, a fast alternative to conventional molecular dynamics. We conduct equilibrium simulations on systems containing 96 Ac-KA(14)K-NH2 peptides over a wide range of temperatures and peptide concentrations using the replica-exchange method. Based on measured values of the heat capacity, radius of gyration, and percentage of peptides that form the various structures, a phase diagram in the temperature-concentration plane is constructed delineating the regions where each structure is stable. There are four distinct single-phase regions: alpha-helices, fibrils, nonfibrillar beta-sheets, and random coils; and four two-phase regions: random coils/nonfibrillar beta-sheets, random coils/fibrils, fibrils/nonfibrillar beta-sheets, and alpha-helices/nonfibrillar beta-sheets. The alpha-helical region is at low temperature and low concentration. The nonfibrillar beta-sheet region is at intermediate temperatures and low concentrations and expands to higher temperatures as concentration is increased. The fibril region occurs at intermediate temperatures and intermediate concentrations and expands to lower as the peptide concentration is increased. The random-coil region is at high temperatures and all concentrations; this region shifts to higher temperatures as the concentration is increased.