Ab initio protein folding simulations using atomic burials as informational intermediates between sequence and structure

Abstract

The three-dimensional structure of proteins is determined by their linear amino acid sequences but decipherment of the underlying protein folding code has remained elusive. Recent studies have suggested that burials, as expressed by atomic distances to the molecular center, are sufficiently informative for structural determination while potentially obtainable from sequences. Here we provide direct evidence for this distinctive role of burials in the folding code, demonstrating that burial propensities estimated from local sequence can indeed be used to fold globular proteins in ab initio simulations. We have used a statistical scheme based on a Hidden Markov Model (HMM) to classify all heavy atoms of a protein into a small number of burial atomic types depending on sequence context. Molecular dynamics simulations were then performed with a potential that forces all atoms of each type towards their predicted burial level, while simple geometric constraints were imposed on covalent structure and hydrogen bond formation. The correct folded conformation was obtained and distinguished in simulations that started from extended chains for a selection of structures comprising all three folding classes and high burial prediction quality. These results demonstrate that atomic burials can act as informational intermediates between sequence and structure, providing a new conceptual framework for improving structural prediction and understanding the fundamentals of protein folding.

Information and redundancy in the burial folding code of globular proteins within a wide range of shapes and sizes

“…As detailed in Ref. 22, the potential contains simple terms on bond lengths, angles, rigid dihedrals and pairwise repulsion, with non-standard terms for burials and hydrogen bond formation, and was derived from the all-atom structure-based model described in Ref. 41, with removal of the native-dependent contact and dihedral energy terms and the addition of terms for hydrogen bonds and atomic burials.…”

“…The hydrogen bond term is annealed linearly during each folding trajectory, a convenient procedure to avoid kinetic trapping at the expense of realistic modeling of path-dependent features of the process, as previously discussed. 22 No annealing is performed in unfolding trajectories, which begin from the native structure with full hydrogen bonds. The intervals in central distances defining each burial layer are presently adjusted to accommodate the same number of atoms in each layer, while the radius within which hydrogen bond formation is enforced is still derived from the radius of gyration for each protein estimated from its number of residues, as in our previous simulations.…”

“…All size-independent parameters are also the same as in this previous investigation. 22 Total simulation time is however 10 times smaller, or 2 3 10 8 instead of 2 3 10 9 time steps, to viabilize both the required large number of simulations for the estimates of available redundancy in small proteins as well as the small number of significantly more demanding simulations for the larger proteins.…”

“…Relative prediction uncertainty, 2hLLi=log 2 L, is plotted as a function of prediction inaccuracy, f, for burial predictions with L 5 4 of 223 small globular proteins with 50 N r 80 obtained by a Hidden Markov Model as described elsewhere. 22 Each point corresponds to a protein. The curve represents H 2 (f) as provided by Eq.…”

“…We have been exploring the possibility that atomic burials, as quantified by central distances, could constitute such messages. 18,[20][21][22] In terms of a simple analogy with human communication, which is actually similar to the one discussed in Ref. 11, we investigate if the set of viable burial sequences could constitute a "language" capable of expressing structural "ideas" while satisfying the "grammar" of sequence-independent constraints and being encodable in the "script" generated by the alphabet of amino acids.…”