Dynamic Monte Carlo simulations of a new lattice model of globular protein folding, structure and dynamics.

A long-standing problem of molecular biology is the prediction of globular protein tertiary structure from the primary sequence. In the context of a new, 24-nearest-neighbor lattice model of proteins that includes both alpha and beta-carbon atoms, the requirements for folding to a unique four-member beta-barrel, four-helix bundles and a model alpha/beta-bundle have been explored. A number of distinct situations are examined, but the common requirements for the formation of a unique native conformation are tertiary interactions plus the presence of relatively small (but not irrelevant) intrinsic turn preferences that select out the native conformer from a manifold of compact states. When side-chains are explicitly included, there are many conformations having the same or a slightly greater number of side-chain contacts as in the native conformation, and it is the local intrinsic turn preferences that produce the conformational selectivity on collapse. The local preference for helix or beta-sheet secondary structure may be at odds with the secondary structure ultimately found in the native conformation. The requisite intrinsic turn populations are about 0.3% for beta-proteins, 2% for mixed alpha/beta-proteins and 6% for helix bundles. In addition, an idealized model of an allosteric conformational transition has been examined. Folding occurs predominantly by a sequential on-site assembly mechanism with folding initiating either at a turn or from an isolated helix or beta-strand (where appropriate). For helical and beta-protein models, similar folding pathways were obtained in diamond lattice simulations, using an entirely different set of local Monte Carlo moves. This argues strongly that the results are universal; that is, they are independent of lattice, protein model or the particular realization of Monte Carlo dynamics. Overall, these simulations demonstrate that the folding of all known protein motifs can be achieved in the context of a single class of lattice models that includes realistic backbone structures and idealized side-chains.