All-atom chain-building by optimizing MODELLER energy function using conformational space annealing.

We have investigated the effect of rigorous optimization of the MODELLER energy function for possible improvement in protein all-atom chain-building. For this we applied the global optimization method called conformational space annealing (CSA) to the standard MODELLER procedure to achieve better energy optimization than what MODELLER provides. The method, which we call MODELLERCSA, is tested on two benchmark sets. The first is the 298 proteins taken from the HOMSTRAD multiple alignment set. By simply optimizing the MODELLER energy function, we observe significant improvement in side-chain modeling, where MODELLERCSA provides about 10.7% (14.5%) improvement for chi(1) (chi(1) + chi(2)) accuracy compared to the standard MODELLER modeling. The improvement of backbone accuracy by MODELLERCSA is shown to be less prominent, and a similar improvement can be achieved by simply generating many standard MODELLER models and selecting lowest energy models. However, the level of side-chain modeling accuracy by MODELLERCSA could not be matched either by extensive MODELLER strategies, side-chain remodeling by SCWRL3, or copying unmutated rotamers. The identical procedure was successfully applied to 100 CASP7 template base modeling domains during the prediction season in a blind fashion, and the results are included here for comparison. From this study, we observe a good correlation between the MODELLER energy and the side-chain accuracy. Our findings indicate that, when a good alignment between a target protein and its templates is provided, thorough optimization of the MODELLER energy function leads to accurate all-atom models. Copyright 2008 Wiley-Liss, Inc.