All‐atom replica exchange molecular simulation of protein BBL

Abstract

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.

Exploiting the downhill folding regime via experiment

“…The wealth of structural unfolding information originating from these experiments provides challenging quality controls for the performance of all atom computer simulations. In particular, two different groups have recently performed replica exchange molecular dynamics simulations in explicit solvent of BBL unfolding (Pitera et al, 2008;Zhang et al, 2008). These simulations are remarkably good in reproducing the overall unfolding behavior of BBL and the large structural heterogeneity observed experimentally.…”

Comparison Between Empirical Protein Force Fields for the Simulation of the Adsorption Behavior of Structured LK Peptides on Functionalized Surfaces

“…There are a large variety of approaches to evaluating the state of convergence of an REMD simulation [41][42][43][44][45][46][47][48], and a consistent metric within all approaches is the convergence of specific system parameters of interest in the simulation. In our simulations, we were primarily concerned with structural features of the peptides and the surrounding solution as they interacted with the surface chemistries presented to them.…”

Dynamics of one-state downhill protein folding

“…Building upon this idea, the 40-residue helical protein BBL has been found to exhibit one-state folding thermodynamics according to a battery of quantitative experimental criteria: (i) probe-dependent equilibrium unfolding (12); (ii) complex coupling between denaturing agents (13); (iii) characteristic DSC thermogram (14); (iv) gradual melting of secondary structure (15); (v) heterogeneous atom-by-atom unfolding behaviors spanning the entire unfolding process (16); and (vi) generalized baseline crossings in fits to global two-state models (17). BBL equilibrium unfolding has also been investigated in molecular simulations, ranging from off-lattice models with Go potentials (18)(19)(20)(21)(22) to replica exchange molecular dynamics (REMD) simulations in explicit solvent (23,24). All simulations indicate that BBL crosses very minimal folding barriers, if any.…”