proteins STRUCTURE O FUNCTION O BIOINFORMATICS Prediction Report High accuracy template based modeling by global optimization Keehyoung Joo, 1 Jinwoo Lee, 1 Sunjoong Lee, 1,2 Joo-Hyun Seo, 1,3 Sung Jong Lee, 4 and Jooyoung Lee 1 * 1 School of Computational Sciences, Korea Institute for Advanced Study, Seoul, Korea 2 Department of Physics, Hanyang University, Ansan, Korea 3 School of Chemical and Biological Engineering, Seoul National University, Seoul, Korea 4 Department of Physics, University of Suwon, Hwaseong-si, Korea INTRODUCTION Through CASP experiments, various template-based modeling methods have been proposed, and the importance of successful template based modeling has been ever increasing. One of the important issues in this cat- egory is to improve the accuracy of the modeling to the level of the experi- ment. The emergence of high accurate template-based modeling (TBM/ HA) category in this CASP7 reflects on this. In this CASP7 experiment, we have applied systematically a powerful global optimization method, the conformational space annealing (CSA), 1 to the whole procedure at three levels: multiple alignment, backbone modeling, and side-chain modeling. The success of this approach depends on the harmony of a powerful optimization method with accu- rate score functions. For this purpose, we have developed a consistency- based score function for multiple alignment so that the more we opti- mize, the more the consistency is satisfied. For chain building and side- chain remodeling, we used MODELLER energy function and an in-house score function similar to the SCWRL3.0 in which we add rotamers gen- erated by consensus analysis. We provide an overall analysis of submitted models for 100 domains in the TBM category especially focusing on 26 domains in TBM/HA cat- egory. On average, excellent backbone modeling as well as side-chain modeling are achieved for TBM/HA targets. The authors state no conflict of interest. *Correspondence to: Jooyoung Lee, School of Computational Sciences, Korea Institute for Advanced Study, Seoul, Korea. E-mail: jlee@kias.re.kr Received 3 March 2007; Revised 8 May 2007; Accepted 17 May 2007 Published online 25 September 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/prot.21628 ABSTRACT For high-accuracy template-based-modeling of CASP7 targets, we have applied a proce- dure based on the rigorous optimization of score functions at three stages: multiple alignment, chain building, and side-chain modeling. We applied the conformational space annealing method to a newly developed consistency based score function for multiple alignment. For chain building, we optimized the MODELLER energy function. For side- chain modeling, we optimized a SCWRL-like energy function using a rotamer library constructed specifically for a given target sequence. By rigorous optimization, we have achieved significant improvement in back- bone as well as side-chain modeling for TBM and TBM/HA targets. For most TBM/HA tar- gets (17/26), the predicted model was more accurate than the model one can construct from the best template in a posteriori fash- ion. It appears that the current method can extract relevant information out of multiple templates. Proteins 2007; 69(Suppl 8):83–89. V V C 2007 Wiley-Liss, Inc. Key words: TBM/HA; template-based model- ing; protein structure prediction; global opti- mization; multiple alignment; side-chain modeling; model evaluation; fold recognition. V V C 2007 WILEY-LISS, INC. PROTEINS 83