Contact-assisted protein structure modeling by global optimization in CASP11

Abstract

We have applied the conformational space annealing method to the contact-assisted protein structure modeling in CASP11. For Tp targets, where predicted residue-residue contact information was provided, the contact energy term in the form of the Lorentzian function was implemented together with the physical energy terms used in our template-free modeling of proteins. Although we observed some structural improvement of Tp models over the models predicted without the Tp information, the improvement was not substantial on average. This is partly due to the inaccuracy of the provided contact information, where only about 18% of it was correct. For Ts targets, where the information of ambiguous NOE (Nuclear Overhauser Effect) restraints was provided, we formulated the modeling in terms of the two-tier optimization problem, which covers: (1) the assignment of NOE peaks and (2) the three-dimensional (3D) model generation based on the assigned NOEs. Although solving the problem in a direct manner appears to be intractable at first glance, we demonstrate through CASP11 that remarkably accurate protein 3D modeling is possible by brute force optimization of a relevant energy function. For 19 Ts targets of the average size of 224 residues, generated protein models were of about 3.6 Å Cα atom accuracy. Even greater structural improvement was observed when additional Tc contact information was provided. For 20 out of the total 24 Tc targets, we were able to generate protein structures which were better than the best model from the rest of the CASP11 groups in terms of GDT-TS. Proteins 2016; 84(Suppl 1):189-199. © 2015 Wiley Periodicals, Inc.

Keywords: NMR structure determination; casp; contact-assisted modeling; global optimization; protein structure modeling; sparse and ambiguous NOE restraint; two-tier optimization.