Template‐free modeling by LEE and LEER in CASP11

Abstract

For the template-free modeling of human targets of CASP11, we utilized two of our modeling protocols, LEE and LEER. The LEE protocol took CASP11-released server models as the input and used some of them as templates for 3D (threedimensional) modeling. The template selection procedure was based on the clustering of the server models aided by a community detection method of a server-model network. Restraining energy terms generated from the selected templates together with physical and statistical energy terms were used to build 3D models. Side-chains of the 3D models were rebuilt using target-specific consensus side-chain library along with the SCWRL4 rotamer library, which completed the LEE protocol. The first success factor of the LEE protocol was due to efficient server model screening. The average backbone accuracy of selected server models was similar to that of top 30% server models. The second factor was that a proper energy function along with our optimization method guided us, so that we successfully generated better quality models than the input template models. In 10 out of 24 cases, better backbone structures than the best of input template structures were generated. LEE models were further refined by performing restrained molecular dynamics simulations to generate LEER models. CASP11 results indicate that LEE models were better than the average template models in terms of both backbone structures and side-chain orientations. LEER models were of improved physical realism and stereo-chemistry compared to LEE models, and they were comparable to LEE models in the backbone accuracy.

Protein structure modeling and refinement by global optimization in CASP12

“…Since then, similar observations were reported by other groups . In CASP11, we tested our own MD‐based refinement protocol (LEER human protocol) and found out that, on average, our refinement protocol improved the protein models generated by our standard human protocol LEE . Based on this observation, we further developed our refinement method to see if we could come up with an improved protocol .…”

“…As described in the METHODS section, for LEE and LEEab modeling, we selected a number of server models as templates from all the server models predicted by CASP12 servers. This procedure included screening, clustering, and identifying the best cluster (see the “LEE/LEEab: Human Protocol” section and our CASP11 publications). The statistics of all the server models used as templates to generate LEE model 1 (LEE1) are shown in Table .…”

“…Since CASP7, we formulated protein 3D modeling in terms of 3 layers of combinatorial optimization problems; multiple sequence alignment, chain building using the alignment containing multiple templates, and side‐chain remodeling . When solving each combinatorial problem, due to the intrinsic nature of solving frustrated systems, obtaining a solution that satisfies all the restraints applied is seemingly impossible.…”

“…For the human prediction of CASP12 targets, we used 2 protocols called LEE and LEEab. The LEE protocol is identical to the GOAL protocol except that, in LEE, server models from every CASP12 participating server were considered as templates . Templates were selected by model screening, clustering the screened models, and identification of the best cluster.…”

Protein structure model refinement in CASP12 using short and long molecular dynamics simulations in implicit solvent

“…The FEIG's approach was based on MD: from the MD trajectories starting of a model to be refined, structures were chosen that did not deviate much from the initial structure to avoid degraded structures and further filtered by using additional scoring function. 20 In CASP11, many top performing groups, including FEIG, 15,21 used MD-based approaches with some variations, for example, using support vector machine (a machine learning method) to select models after MD, 22 remodeling using multiple templates before MD-based refinement, 23 taking consensus with homologous structures, 24 or using multiple rounds of relaxation. 25 Here, we report our group's method and performance in the model refinement category in CASP12.…”