All-atom replica exchange molecular simulation of protein BBL

Downhill folding is one of the most important predictions of energy landscape theory. Recently, the Escherichia coli 2-oxoglutarate dehydrogenase PSBD was described as a first example of global downhill folding (Garcia-Mira et al., Science 2002,298:2191), classification that has been later subject of significant controversy. To help resolve this problem, by using intensive all-atom simulation with explicit water model and the replica exchange method, we sample the phase space of protein BBL and depict the free energy landscape. We give an estimate of the free energy barrier height of 1-2 k(B)T, dependent on the way the energy landscape is projected. We also study the conformational distribution of the transition region and find that the three helices generally take the similar positions as that in the native states whereas their spatial orientations show large variability. We further detect the inconsistency between different signals by individually fitting the thermal denaturation curves of five structural features using two-state model, which gives a wide spread melting temperature of 19 K. All of these features are consistent with a picture of folding with very low cooperativities. Compared with the experimental data (Sadqi et al., Nature 2006; 442:317), our results indicate that the Naf-BBL (pH5.3) may have an even lower barrier height and cooperativity,