Modeling amyloid fibril formation: a free-energy approach

Amyloid fibrils are structures consisting of many proteins with a well-defined conformation. The formation of these fibrils has been the subject of intense research, largely due to their connection to several diseases. We focus here on the computational studies and discuss these from a free-energy point of view. The fibrillogenic properties of many proteins can be predicted and understood by taking the relevant free energies into account in an appropriate way. This is because both the equilibrium and the kinetic properties of the protein system depend on its free-energy landscape. Advanced simulation techniques can be used to understand the relationship between the free-energy landscape of a protein and its three-dimensional structure and propensity to form amyloid fibrils. We give an overview of existing simulation techniques that operate at a molecular level of detail and that are capable of generating relevant free-energy values. The free energies obtained with these methods can be inserted into a statistical-mechanical or kinetic framework to predict mean fibril properties on length scales and time scales that are inaccessible by molecular-scale simulation methods.