A challenge in computational protein folding is to
assemble secondary structure elements—helices and
strands—into well-packed tertiary structures. Particularly
difficult is the formation of β-sheets from strands,
because they involve large conformational searches at the
same time as precise packing and hydrogen bonding. Here we
describe a method, called Geocore-2, that (1) grows chains
one monomer or secondary structure at a time, then (2)
disconnects the loops and performs a fast rigid-body docking
step to achieve canonical packings, then (3) in the case of
intrasheet strand packing, adjusts the side-chain rotamers;
and finally (4) reattaches loops. Computational efficiency
is enhanced by using a branch-and-bound search in which pruning
rules aim to achieve a hydrophobic core and satisfactory
hydrogen bonding patterns. We show that the pruning rules reduce
computational time by 103- to 105-fold,
and that this strategy is computationally practical at least
for molecules up to about 100 amino acids long.