Conformational Isomerism - Protein Rotamer Libraries

Protein Rotamer Libraries

A rotamer library is a collection of the energetically favorable conformations for each residue type in proteins, specifying the value of all side-chain degrees of freedom (the dihedral angles). Rotamer libraries usually contain information about both conformation and frequency of a certain conformation. Often libraries will also contain information about the variance about dihedral angle means or modes, which can be used in sampling. Rotamer libraries are used both for protein design and crystallographic model building, in which case the central position and its frequency is most important, and also in structure validation, in which case the outer edges of the distribution are critical for identifying possibly incorrect outliers.

Side-chain dihedral angles are not evenly distributed, and for most side chain types, the angles occur in tight clusters around certain values. Rotamer libraries therefore are usually derived from statistical analysis of side-chain conformations in known structures of proteins by clustering observed conformations or by dividing dihedral angle space into bins, and determining an average conformation in each bin. This division is usually on physical-chemical grounds, as in the divisions for rotation about sp3-sp3 bonds into three 120° bins centered on each staggered conformation (60°, 180°, -60°).

Rotamer libraries can be backbone-independent, secondary-structure-dependent, or backbone-dependent. The distinctions are made depending on whether the dihedral angles for the rotamers and/or their frequencies depend on the local backbone conformation or not. Backbone-independent rotamer libraries make no reference to backbone conformation, and are calculated from all available side chains of a certain type. Secondary-structure-dependent libraries present different dihedral angles and/or rotamer frequencies for -helix, -sheet, or coil secondary structures. Backbone-dependent rotamer libraries present conformations and/or frequencies dependent on the local backbone conformation as defined by the backbone dihedral angles and, regardless of secondary structure. Finally, a variant on backbone-dependent rotamer libraries exists in the form of position-specific rotamers, those defined by a fragment usually of 5 amino acids in length, where the central residue’s side chain conformation is examined.