Constrained Layer Assignment for the Protein Burial Folding Code Accounting for Chain Connectivity.

Abstract

The connection between protein sequences and tertiary structures has intrigued investigators for decades. A plausible hypothesis for the coding scheme postulates that atomic burial information obtainable from the sequence could be sufficient for structural determination when combined to sequence-independent constraints. Accordingly, folding simulations using native burial information expressed by atomic central distances, discretized into a small number L of equiprobable burial layers, have indeed been successful in reaching and distinguishing the native structure of several globular proteins. Attempted predictions of layers from sequence, however, turned out to be insufficiently accurate for most proteins. Here we explore the possibility that a nonuniform assignment of layers, which is intended to account for constraints imposed by chain connectivity, might provide a more efficient burial encoding of tertiary structures. We consider the condition that adjacent Cα-atoms along the sequence cannot occupy nonadjacent layers, in which case the information required to specify sequences of burials would be smaller. It is shown that appropriate folding behavior can still be observed in this explicitly more constrained scenario with a structure-dependent assignment intended to produce the thinnest possible layers still compatible with the imposed burial constraint. This thinnest assignment turns out to be sufficiently restrictive for the observed examples and provides appropriately thinner layers or, equivalently, a larger number of layers, for examples previously observed to indeed require more restrictive constraints when compared to counterparts of similar size, as well as the appropriate increase in number of layers for larger proteins. Implications for the general understanding of the protein folding code are discussed.