TetraBASE: A Side Chain-Independent Statistical Energy for Designing Realistically Packed Protein Backbones

Abstract

To construct backbone structures of high designability is a primary aspect of computational protein design. We report here a side chain-independent statistical energy that aims at realistic modeling of through-space packing of polypeptide backbones. To mitigate the lack of explicit amino acid side chains, the model treats the interbackbone site packing as being dependent on peptide local conformation. In addition, new variables suitable for statistical analysis, one for relative orientation and another for distance, have been introduced to represent the intersite geometry based on the asymmetrical tetrahedron organization of distinct chemical groups surrounding the Cα-carbon atoms. The resulting tetrahedron-based backbone statistical energy (tetraBASE) model has been used to optimize the tertiary organizations of secondary structure elements (SSEs) of designated types with Monte Caro simulated annealing, starting from artificial initial configurations. The tetraBASE minimum energy structures can reproduce SSE packing frequently observed in native proteins with atomic root-mean-square deviations of 1-2 Å. The model has also been tested by examining the stability of native SSE arrangements under tetraBASE. The results suggest that tetraBASE model can be used to effectively represent interbackbone packing when designing backbone structures without explicitly knowing side chain types.