Modeling protein structure as a stable static equilibrium.

Abstract

We present evidence that the protein structure can be modeled as a stable static equilibrium, determined mainly by compressive supports in the nonpolar interior. That is, protein structures derive their structural strength through the same mechanical principles as do conventional structures like bridges and buildings. This is based on the observation that the experimentally elucidated structural determinants, the interior nonpolar side chains, are engaged in strong compressions in static terms. At the same time, major substructures in proteins, helices and h-bonded strands, because of their geometry, inherently leave gaps in the space they occupy. Under the compressive force, nonpolar side chains from one substructure can protrude into the gaps of another neighboring substructure and block its motion. As a result, interlocking of substructures can form, which builds up the nonpolar core assembly. The native structure then is the one with the structurally most stable core assembly. While intuitively appealing, this is a radical departure from the prevailing thinking that protein native structure is determined by global energy minimum, which is founded on thermodynamic hypothesis. Furthermore, to develop an effective model for analyzing protein structure with conventional tools, a proper mechanical representation must be established. By proving that the stability of the equilibrium in compressive interactions is conditioned on a form of mechanical energy minimum, we show that our notion of native structure can be equally consistent with the thermodynamic hypothesis. By mathematically treating the blocking action, an interaction, as a bar, a physical object, we succeed in representing and analyzing the core assembly as truss, a conventional structure. In this paper we define and expound step-by-step increasingly integrated interlocking patterns. We then analyze the core assemblies of a large set of diverse protein database structures. A native structure can be distinguished from decoys by comparing the composition and strength of their core assemblies. We show the results for two sets of native structures vs decoys.