ENHANCED DEAD-END ELIMINATION IN THE SEARCH FOR THE GLOBAL MINIMUM ENERGY CONFORMATION OF A COLLECTION OF PROTEIN SIDE-CHAINS

Although the conformational states of protein side chains can be descr ibed using a library of rotamers, the determination of the global mini mum energy conformation (GMEC) of a large collection of side chains, g iven fixed backbone coordinates, represents a challenging combinatoria l problem with important applications in the field of homology modelli ng, Recently, we have developed a theoretical framework, called the de ad-end elimination method, which allows us to identify efficiently rot amers that cannot be members of the GMEC, Such dead-ending rotamers ca n be iteratively removed from the system under study thereby tracking down the size of the combinatorial problem, Here we present new develo pments to the dead-end elimination method that allow us to handle larg er proteins and more extensive rotamer libraries, These developments e ncompass (i) a procedure to determine weight factors in the generalize d dead-end elimination theorem thereby enhancing the elimination of de ad-ending rotamers and (ii) a novel strategy, mainly based on logical arguments derived from the logic pairs theorem, to use dead-ending rot amer pairs in the efficient elimination of single rotamers, These deve lopments are illustrated for proteins of various sizes and the flow of the current method is discussed in detail, The effectiveness of dead- end elimination is increased by two orders of magnitude as compared wi th previous work, In addition, it now becomes feasible to use extremel y detailed libraries, We also provide an appendix in which the validit y of the generalized dead-end criterion is shown, Finally, perspective s for further applications which may now become within reach are discu ssed.