Interplaying Roles of Native Topology and Chain Length in Marginally Cooperative and Noncooperative Folding of Small Protein Fragments

Coarse-grained chain simulations were used to study fragments of two homologous proteins of the peripheral subunit-binding domain (PSBD) family, Bacillus stearothermophilus PSBD (E3BD) and Escherichia coli 2-oxo-glutarate dehydrogenase PSBD (BBL). To ascertain a robust rank order of folding cooperativity, native-centric intraprotein interactions were modeled by (i) a common Gō-like potential, and (ii) native-centric potentials with desolvation barriers or (iii) many-body terms. Homologous proteins can possess substantially different folding cooperativity. Consistent with experiment, our calculations indicated that E3BD fragments fold more cooperatively than BBL fragments of approximately the same chain length. For a given fragment, native contacts deduced from Protein Data Bank structures can vary significantly depending on the number of residues that the structure encompasses in addition to those of the fragment itself, resulting in variation in model folding cooperativity predicted using different native contact sets for the Correspondence to: H. S. Chan; e-mail: [email protected]. toronto.edu Artem Badasyan is currently at Dipartimento di Chimica Fisica, Facoltà di Scienze, Università Ca’ Foscari di Venezia, Calle Larga S. Marta DD2137, I-30123 Venezia, Italy. Zhirong Liu is currently at College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. Contract grant sponsor: The Canadian Institutes of Health Research (CIHR). Contract grant number: MOP-84281. International Journal of Quantum Chemistry, Vol 109, 3482–3499 (2009) © 2009 Wiley Periodicals, Inc. NONCOOPERATIVE FOLDING OF SMALL PROTEINS same fragment. This observation underscores that folding cooperativity of these fragments can be extremely sensitive to change in chain length. Thus, a ∼40-residue protein fragment’s folding cooperativity, or lack thereof, does not necessarily imply essentially identical behaviors for superor sub-fragments with only several residues more, or less, than the given fragment. Ramifications for experimental investigations of downhill folding are discussed. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem 109: 3482–3499, 2009