A fast loop-closure algorithm to accelerate residue matching in computational enzyme design.

Constructing an active site on an inert scaffold is still a challenge in chemical biology. Herein, we describe the incorporation of a Newton-direction-based fast loop-closure algorithm for catalytic residue matching into our enzyme design program ProdaMatch. This was developed to determine the sites and geometries of the catalytic residues as well as the position of the transition state with high accuracy in order to satisfy the geometric constraints on the interactions between catalytic residues and the transition state. Loop-closure results for 64,827 initial loops derived from 21 loops in the test set showed that 99.51% of the initial loops closed to within 0.05 Å in fewer than 400 iteration steps, while the large majority of the initial loops closed within 100 iteration steps. The revised version of ProdaMatch containing the novel loop-closure algorithm identified all native matches for ten scaffolds in the native active-site recapitulation test. Its high speed and accuracy when matching catalytic residues with a scaffold make this version of ProdaMatch potentially useful for scaffold selection through the incorporation of more complex theoretical enzyme models which may yield higher initial activities in de novo enzyme design.