Rotamer searches

C Wilson, LM Gregoret, DA Agard. Modeling side-chain conformation for homologous proteins using an energy-based rotamer search. J Mol Biol 229 996-1006, 1993. 

Considering only the conformations with a total energy less than 10 kJ mol" above the lowest energy conformations, the same ensemble of conformations as detected in the structural database searches was found. With this systematic backbone and side chain rotamer search approach, we analysed only 144 structures instead of the 10 structures for a conventional grid search with 36° intervals for 6 dihedral angles. 

The latest developments in modeling are position-specific rotamer searches (Fig. 2). Dunbrack et al. and Vriend et al. showed that the preferred rotamer is to a large extent determined by a local backbone [34,35], Database searches for peptides with the same local backbone and the same amino acid type in the middle often reveal a more restricted pattern of side-chain conformations than one would expect from generalized rotamer libraries. Position-specific rotamer distributions are obtained by searching the database for segments of residues that fulfill two criteria ... 

Side chain generation is often a source of error. It will be most reliable if certain rules of thumb are obeyed. Start with structurally conserved side chains and hold them fixed. Then look at the energy and entropy of rotamers for the remaining side chains. Conventional conformation search techniques are often used to place each side chain. 

Fig. 22 A depiction of the rotations of the carboxylic acid group on (S)-linarinic acid responsible for the lowest-energy rotamers found in the conformational search considering water-linarinic acid clusters in Ref. [166]...

A more efficient search protocol, developed by Wernisch et al. [40], intermixes sequence and structure changes more intimately, in a heuristic way. A heuristic cycle consists in the following steps. First, the amino acid type and rotamer at each position (or a large subset of positions) are randomized. Then, an iterative, steepest descent minimization is performed. The best amino acid type and rotamer are identified at the first position (given the current values at all the other positions) the best combination at the second position is identified, and so on. Each position is considered in turn, and multiple passes through the sequence are performed in this... 

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