Lock-picking analogy for high-resolution protein loop structure prediction.

(a) Starting conformation for loop structure prediction (left panel) includes the crystallographic backbone outside the excised loop (white; gray spheres mark loop boundaries) and side-chains in potentially incorrect configurations (white and green). The situation is analogous to a pin tumbler lock (right panel) with spring-loaded pin doublets (green & pink cylinders) in relaxed configurations that disallow turning of the lock cylinder (gray, in cut-away view). (b) Atomic-accuracy solution for protein loop (left panel) involves precise fit of loop backbone (gold) and side-chains (pink) to surrounding protein. Several surrounding side-chains (green) have switched conformations. The solution is analogous to a key (right panel) that precisely slides up the pin doublets so that the boundaries between top and bottom pins coincide with the boundary of lock cylinder, which can then be turned. (c) ‘Stepwise ansatz’ involves residue-by-residue build-up of the protein loop (gold and pink), with fine, all-atom enumerative search of loop conformations (red arrows mark some of the backbone torsions searched) and surrounding side-chains (green) at each step. The strategy is analogous to picking a tumbler lock with a probing pick (gold, right panel) that finely sets the tumbler pins into the turnable configuration through pin-by-pin fine search. [A wrench (light gray) applying torsion to the cylinder helps trap each pin at the boundary].