Thermodynamics and kinetics of downhill protein folding investigated with a simple statistical mechanical model

The possibility of downhill protein folding is one of the most intriguing predictions of the energy landscape approach. Finding examples of downhill folding has important practical implications because in the absence of a free energy barrier the mechanism of folding is amenable to experimental observation, Here, a simple statistical mechanical model of protein folding is used to analyze the thermodynamic and kinetic properties of downhill and two-state folding. Folding free energy surfaces with an Without a barrier separating denatured and native states can be generated with this model by simply modifying the curvature of the energy as a function of the order parameter, i.e., number of amino acids in incorrect conformation. Thermodynamic and kinetic analysis of surfaces with a barrier show the typical properties of two-state folding: a first-order equilibrium unfolding transition and exponential biphasic folding kinetics. In contrast, in downhill surfaces the unfolding process is noncooperative, and the apparent transition depends on the structural probe used to measure it. Therefore, this inherent behavior can be used as an experimental criterion for the identification of downhill folding, surprisingly, the kinetics of downhill folding do not greatly deviate from exponential behavior unless the effective diffusion coefficient is assumed to decrese as folding progresses, exemplifying the increase in the roughness of the landscape. (C) 2002 Wiley Periodicals, Inc.