THE ORIGINS OF PROTEIN SECONDARY STRUCTURE - EFFECTS OF PACKING DENSITY AND HYDROGEN-BONDING STUDIED BY A FAST CONFORMATIONAL SEARCH

Globular proteins fold to create compact structures rich in a-helices and beta-sheets. While studies of cubic lattice models of simplified p olypeptide chains have concluded that secondary structure is a necessa ry consequence of chain compactness, different conclusions have been r eached from studies of off-lattice models of simplified chains. In an attempt to resolve this controversy, we study an all-atom off-lattice model of a protein subject to a variety of simplified energy functions . A Monte Carlo simulated annealing algorithm is used to search confor mational space quickly. The algorithm uses pivot-type moves in which a residue is selected. at random and the values of its main-chain dihed ral angles are changed. The energy function used to accept or reject m oves is taken to be either a term proportional to the volume occupied by a structure (to mimic the hydrophobic effect), a term proportional to the energy of main-chain hydrogen bonding, or a combination of thes e two terms. Secondary structure content is evaluated using several di fferent definitions. For all the definitions used, compactness alone p roduces a 10% increase in secondary structure content. However, this i s a small fraction of the secondary structure observed in native prote in structures. Structures produced by minimizing the hydrogen bond ene rgy have extensive secondary structure but are not densely packed. Str uctures having both the high density of native structures and extensiv e secondary structure are produced by minimizing combinations of the v olume and hydrogen bond energy terms. Our results emphasize the close relationship between secondary structure and the geometry of main-chai n hydrogen bonding. The results are consistent with a description of p rotein folding in which the hydrophobic effect favors dense packing wh ile hydrogen bonding determines the specific local geometry which gene rates secondary structure. To make an analogy with lattice studies of packing density and secondary structure, it seems that hydrophobicity provides the packing density while hydrogen bonding provides the latti ce.