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 combined to generate 3‐dimensional conformations of protein loop segments. The computational efficiency and sensitivity to initial loop copy dispersion are analyzed. The multicopy loop modeling method requires approximately 20‐50% of the computational time required by the single‐copy method for the various protein segments tested. An analytical formula is proposed to estimate the computational gain prior to carrying out a multicopy simulation. When 7‐residue loops within flexible proteins are modeled, each multicopy simulation can sample a set of loop conformations with initial dispersions up to ±15° for backbone and ±3° for side‐chain rotatable dihedral angles. The dispersions are larger for shorter and smaller for longer and/or surface loops. 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 flexibility of the modeled protein segment. Application to simultaneously building all 6 hypervariable loops of an antibody is discussed.