Observation of non-cooperative folding thermodynamics in simulations of 1BBL
Jed W Pitera 1*, William C Swope 1 and Farid F Abraham 2
1 IBM Research
2 LLNL
* To whom correspondence should be addressed. E-mail: pitera{at}us.ibm.com.
Submitted on October 3, 2007
Revised on November 14, 2007
Accepted on 8 February 2008
 |
Abstract |
|---|
One of the predictions of the energy landscape theory of protein folding is the possibility of barrier-less, "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 have carried out extensive replica exchange molecular dynamics simulations on 1BBL in explicit solvent in order 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. While our simulations cannot provide definitive evidence of "downhill" folding in 1BBL, they clearly show evidence of a complex, non-two-state folding process.
Key Words:
PSBD, downhill folding, molecular dynamics, one-state folding, replica-exchange, two-state folding
