ALL-IN-ONE - A HIGHLY DETAILED ROTAMER LIBRARY IMPROVES BOTH ACCURACYAND SPEED IN THE MODELING OF SIDE-CHAINS BY DEAD-END ELIMINATION

Background: About a decade ago, the concept of rotamer libraries was i ntroduced to model sidechains given known mainchain coordinates. Since then, several groups have developed methods to handle the challenging combinatorial problem that is faced when searching rotamer libraries. To avoid a combinatorial explosion, the dead-end elimination method d etects and eliminates rotamers that cannot be members of the global mi nimum energy conformation (GMEC). Several groups have applied and furt her developed this method in the fields of homology modelling and prot ein design. Results: This work addresses at the same time increased pr ediction accuracy and calculation speed improvements. The proposed enh ancements allow the elimination of more than one-third of the possible rotameric states before applying the dead-end elimination method. Thi s is achieved by using a highly detailed rotamer library allowing the safe application of an energy-based rejection criterion without riskin g the elimination of a GMEC rotamer. As a result, we gain both in mode lling accuracy and in computational speed. Being completely automated, the current implementation of the dead-end elimination prediction of protein sidechains can be applied to the modelling of sidechains of pr oteins of any size on the high-end computer systems currently used in molecular modelling. The improved accuracy is highlighted in a compara tive study on a collection of proteins of varying size for which score results have previously been published by multiple groups. Furthermor e, we propose a new validation method for the scoring of the modelled structure versus the experimental data based upon the volume overlap o f the predicted and observed sidechains. This overlap criterion is dis cussed in relation to the classic RMSD and the frequently used +/-40 d egrees window in comparing chi 1 and chi 2 angles. Conclusions: We hav e shown that a very detailed library allows the introduction of a safe energy threshold rejection criterion, thereby increasing both the exe cution speed and the accuracy of the modelling program. We speculate t hat the current method will allow the sidechain prediction of medium-s ized proteins and complex protein interfaces involving up to 150 resid ues on low-end desktop computers.