MULTIPLE COPY SAMPLING IN PROTEIN LOOP MODELING - COMPUTATIONAL-EFFICIENCY AND SENSITIVITY TO DIHEDRAL ANGLE PERTURBATIONS

Multiple copy sampling and the bond scaling-relaxation technique are c ombined to generate 3-dimensional conformations of protein loop segmen ts. The computational efficiency and sensitivity to initial loop copy dispersion are analyzed. The multicopy loop modeling method requires a pproximately 20-50% of the computational time required by the single-c opy method for the various protein segments tested. An analytical form ula is proposed to estimate the computational gain prior to carrying o ut a multicopy simulation. When 7-residue loops within flexible protei ns are modeled, each multicopy simulation can sample a set of loop con formations with initial dispersions up to +/-15-degrees for backbone a nd +/-30-degrees for side-chain rotatable dihedral angles. The dispers ions are larger for shorter and smaller for longer and/or surface loop s. The degree of convergence of loop copies during a simulation can be used to complement commonly used target functions (such as potential energy) for distinguishing between native and misfolded conformations. Furthermore, this convergence also reflects the conformational flexib ility of the modeled protein segment. Application to simultaneously bu ilding all 6 hypervariable loops of an antibody is discussed.