Toward an Unified Description for Thermodynamics, Folding Kinetics, an…
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"A multiscale-heterogeneous protein energy function was developed for the biophysical study of the thermodynamics, folding kinetics, and mutagenesis of proteins. After hybridizing an atomic force-field into a coarse-grained energy function to account for the specificity of a sequence of amino acids even with the high structural homology, we constructed an exact free energy landscape of a given protein and characterized its thermodynamics and folding-unfolding kinetics via a Chevron plot based on solving exactly a master equation, which would enable us to pursue a mutagenesis application. Our approach was applied successfully for resolving a controversy about the folding mechanism of fast folding proteins.
Recent experiments claiming that BBL protein follows a global downhill folding raised an important controversy as to the folding mechanism of fast folding proteins. Under the global downhill folding scenario not only proteins undergo a gradual folding, but also folding events along the continuous folding pathway could be mapped out from the equilibrium denaturation experiment. Based on the exact calculation using a free energy landscape, relaxation eigenmodes from a master equation, and Monte Carlo simulation of an extended Munoz-Eaton model that incorporates multiscale-heterogeneous pairwise-interactions between amino acids, here we show that the very nature of a two-state cooperative transition such as a bimodal distribution from an exact free energy landscape and biphasic relaxation kinetics do manifest in the thermodynamics and folding-unfolding kinetics of BBL and peripheral subunit-binding domain (PSBD) homologue. Our results provide an unequivocal resolution to the fundamental controversy related to the global downhill folding scheme, whose applicability to other proteins should be critically re-examined. "
Recent experiments claiming that BBL protein follows a global downhill folding raised an important controversy as to the folding mechanism of fast folding proteins. Under the global downhill folding scenario not only proteins undergo a gradual folding, but also folding events along the continuous folding pathway could be mapped out from the equilibrium denaturation experiment. Based on the exact calculation using a free energy landscape, relaxation eigenmodes from a master equation, and Monte Carlo simulation of an extended Munoz-Eaton model that incorporates multiscale-heterogeneous pairwise-interactions between amino acids, here we show that the very nature of a two-state cooperative transition such as a bimodal distribution from an exact free energy landscape and biphasic relaxation kinetics do manifest in the thermodynamics and folding-unfolding kinetics of BBL and peripheral subunit-binding domain (PSBD) homologue. Our results provide an unequivocal resolution to the fundamental controversy related to the global downhill folding scheme, whose applicability to other proteins should be critically re-examined. "
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