MacroModel Reference Manual - ISP

Chapter 4: Operation CodesLOOP generates candidate structures in two stages:• Initial loop generation via random selection of rotatable dihedral angles without concernfor loop closure• “Tweak,” an iterative process involving the systematic adjustment of the rotatable bondsto attain loop closure [31, 32] while eliminating very close encounters amongst heavyatoms.In the loop generation stage, the N-terminus and C-terminus halves of the loop are constructedseparately, starting from their attachment points, by growing the chain out to the next rotatablebond. Then a random dihedral angle is chosen for this bond and the heavy atoms positionedunambiguously as a result are checked for close approaches with heavy atoms in the rest of theprotein (not the loop itself). If there are such close approaches, the process of selecting a newrandom angle and checking for close approaches is repeated until either N try such attempts aremade or no close approaches result. If N try such attempts fail then the loop construction processretreats back to the previous rotatable bond for which a new random angle is chosen. When adihedral angle has been chosen successfully, the process focuses on the next rotatable bond outfrom the attachment point. Rotatable bonds in side chains are also sampled in this manner. Theloop generation stage produces a random structure for the protein loop that is not connected inthe middle and does not have close approaches between the loop atoms and the rest of theprotein, but there may such close approaches within the loop itself.In the second stage the Tweak algorithm is used to bring the middle of the loop together in theright geometry. Briefly, this algorithm proceeds by iteratively selecting a set of minimalchanges to the rotatable bonds that lead toward loop closure based upon a linear approximation.Loop closure is specified by a set of target distances that must be met to within a toleranceof 0.001 Angstroms. Along the way close approaches involving heavy atoms of the loop atomsand the rest of the protein are removed by temporarily introducing additional target distancesbetween the overlapping atoms. When the set of distances for closing the loop are met towithin 1 Angstrom the Tweak algorithm also attempts to remove close approaches amongst theheavy atoms within the loop. By using a minimal set of changes to the rotatable bonds theTweak algorithm retains as much of the original, random loop conformation in torsional spaceas possible and thus provides a mechanism for generating a diverse set of candidate loop structures.Limitations:• Only one loop can be treated, although successive calculations may target different loops.• An all-atom representation of the protein must be used.• The protein loop and the residues that it is immediately attached to must consist of alphaamino acids.94MacroModel 9.7 Reference Manual