Miminalist models of proteins: Misfolding and folding affinity

Studies of prions and amyloidogenic proteins provide evidence that proteins may adopt multiple long-lived states in addition to the native state. Wild-type proteins exhibiting this two-state behavior are modeled using a minimalist protein—a lattice 27-monomer heteropolymer sequence consisting of 3 types of monomers—in order to explore the dynamics of systems with multiple long-lived states. A new order parameter—the winding index—is introduced to characterize the extent of folding. The results for the designed model prion protein prove by existence that the rugged energy landscape picture of protein folding can be generalized to include protein “misfolding” into long-lived states.; The weak energetic frustration in protein native structures varies among different proteins and may account for folding behavior not seen in unfrustrated models—i.e., misfolding to long-lived states. The model proteins described above contain weak energetic frustration in their native structures, and their equilibrium and nonequilibrium properties reveal some of the breadth in their behavior. In this work, four model protein structures (with their cognate sequences), selected according to the value of their winding index, exhibit a broad range of folding behavior. Simulation results motivate the definition of a new measure of folding affinity as a rearrangement enthalpy—a function of both the stability gap and accessibility to non-native structures—that correlates strongly with folding rates.; To model real proteins that preferentially misfold under some conditions, free energy landscapes are designed to reduce the folding affinity in one folding funnel of the model prion protein. Simulations on the asymmetric energy landscapes show that the height and location of the barrier between the two folding funnels do not impact the folding rates or the equilibrium populations of the long-lived states, most likely because the barrier between the two funnels is not involved in the rate-determining step of protein folding. Raising the energy of one of the long-lived states reduces its equilibrium population with no impact on the folding rate. Presumably, a model that alters the barrier location and/or height of the rate-determining step—from the molten globule to the long-lived structure—will exhibit prion-like behavior.