Robustness of atomistic Go models in predicting native-like folding intermediates.

Go models are exceedingly popular tools in computer simulations of protein folding. These models are native-centric, i.e., they are directly constructed from the protein's native structure. Therefore, it is important to understand up to which extent the atomistic details of the native structure dictate the folding behavior exhibited by Go models. Here we address this challenge by performing exhaustive discrete molecular dynamics simulations of a Go potential combined with a full atomistic protein representation. In particular, we investigate the robustness of this particular type of Go models in predicting the existence of intermediate states in protein folding. We focus on the N47G mutational form of the Spc-SH3 folding domain (x-ray structure) and compare its folding pathway with that of alternative native structures produced in silico. Our methodological strategy comprises equilibrium folding simulations, structural clustering, and principal component analysis.

Identification of a conserved aggregation-prone intermediate state in the folding pathways of Spc-SH3 amyloidogenic variants.

We compared the folding pathways of selected mutational variants of the α-spectrin SH3 domain (Spc-SH3) by using a continuum model that combines a full atomistic protein representation with the Go potential. Experimental data show that the N47G mutant shows very little tendency to aggregate while the N47A and triple mutant D48G(2Y) are both amyloidogenic, with the latter being clearly more aggregation prone. We identified a strikingly similar native-like folding intermediate across the three mutants, in which strand ß(1) is totally unstructured and more than half of the major hydrophobic core residues are highly solvent exposed. Results from extensive docking simulations show that the ability of the intermediates to dimerize is largely driven by strand ß(1) and is consistent with the in vitro aggregation behavior reported for the corresponding mutants. They further suggest that residues 44 and 53, which are key players in the nucleation-condensation mechanism of folding, are also important triggers of the aggregation process.

The Kohn-Sham density of states and band gap of water: from small clusters to liquid water.

Electronic properties of water clusters (H2O)(n), with n=2, 4, 8, 10, 15, 20, and 30 molecules were investigated by sequential Monte Carlo/density-functional theory (DFT) calculations. DFT calculations were carried out over uncorrelated configurations generated by Monte Carlo simulations of liquid water with a reparametrized exchange-correlation functional that reproduces the experimental information on the electronic properties (first ionization energy and highest occupied molecular orbital-lowest unoccupied molecular orbital gap) of the water dimer. The dependence of electronic properties on the cluster size (n) shows that the density of states (DOS) of small water clusters (n>10) exhibits the same basic features that are typical of larger aggregates, such as the mixing of the 3a1 and 1b1 valence bands. When long-ranged polarization effects are taken into account by the introduction of embedding charges, the DOS associated with 3a1 orbitals is significantly enhanced. In agreement with valence-band photoelectron spectra of liquid water, the 1b1, 3a1, and 1b2 electron binding energies in water aggregates are redshifted by approximately 1 eV relative to the isolated molecule. By extrapolating the results for larger clusters the threshold energy for photoelectron emission is 9.6+/-0.15 eV (free clusters) and 10.58+/-0.10 eV (embedded clusters). Our results for the electron affinity (V0=-0.17+/-0.05 eV) and adiabatic band gap (E(G,Ad)=6.83+/-0.05 eV) of liquid water are in excellent agreement with recent information from theoretical and experimental works.