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Observation of Noncooperative Folding Thermodynamics in Simulations of 1BBL

Jed W. Pitera ^*, William C. Swope ^* and Farid F. Abraham 

^* IBM Almaden Research Center, San Jose, California 95120; and Chemistry, Materials, and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94551

Correspondence: Address reprint requests to Jed W. Pitera, IBM Almaden Research Center, 650 Harry Road, San Jose, CA 95120. Tel.: 408-927-2084; E-mail: pitera{at}us.ibm.com.

One of the predictions of the energy landscape theory of protein folding is the possibility of barrierless, "downhill" folding under certain conditions. The protein 1BBL has been proposed to fold by such a downhill mechanism, though this is a matter of some dispute. We carried out extensive replica exchange molecular dynamics simulations on 1BBL in explicit solvent to address this controversy and provide a microscopic picture of its folding thermodynamics. Our simulations show two distinct structural transitions in the folding of 1BBL. A low-temperature transition involves a disordering of the protein's tertiary structure without loss of secondary structure. A distinct, higher temperature transition involves the complete loss of secondary structure and dissolution of the hydrophobic core. In contrast, control simulations of the 1BBL homolog E3BD show a single high temperature unfolding transition. Further simulations of 1BBL at high ionic strength show a significant destabilization of helix II but not helix I, suggesting that the apparent folding cooperativity of 1BBL may be highly dependent on experimental conditions. Although our simulations cannot provide definitive evidence of downhill folding in 1BBL, they clearly show evidence of a complex, non-two-state folding process.