Side-Chains with Rotamer Library

Side-Chains with Rotamer Library (SCWRL)... 

Once all of the side chains have been constructed, an iterative procedure is employed whereby each residue is considered in turn, and its energy of interaction of all possible rotamers of its side chain with all of the other residues side chains and backbone atoms is calculated. If another rotamer in the library has a lower energy, then it is selected in place of the existing rotamer. This iteration is repeated until an entire cycle over all of the residues in the protein is completed without a single residue being replaced. 

Analysis and prediction of side-chain conformation have long been predicated on statistical analysis of data from protein structures. Early rotamer libraries [91-93] ignored backbone conformation and instead gave the proportions of side-chain rotamers for each of the 18 amino acids with side-chain dihedral degrees of freedom. In recent years, it has become possible to take account of the effect of the backbone conformation on the distribution of side-chain rotamers [28,94-96]. McGregor et al. [94] and Schrauber et al. [97] produced rotamer libraries based on secondary structure. Dunbrack and Karplus [95] instead examined the variation in rotamer distributions as a function of the backbone dihedrals ( ) and V /, later providing conformational analysis to justify this choice [96]. Dunbrack and Cohen [28] extended the analysis of protein side-chain conformation by using Bayesian statistics to derive the full backbone-dependent rotamer libraries at all... 

If the sequence of a protein has more than 90% identity to a protein with known experimental 3D-stmcture, then it is an optimal case to build a homologous structural model based on that structural template. The margins of error for the model and for the experimental method are in similar ranges. The different amino acids have to be mutated virtually. The conformations of the new side chains can be derived either from residues of structurally characterized amino acids in a similar spatial environment or from side chain rotamer libraries for each amino acid type which are stored for different structural environments like beta-strands or alpha-helices. 

SCWRL uses an alternative strategy, based on a probabilistic potential based on the backbone-dependent rotamer library. There are two terms the internal side-chain energy and the local side-chain-backbone interaction are modeled with an energy term proportional to —In prot where prot is the probability of the rotamer for the particular side-chain type and backbone conformation and a simple truncated linear steric term that models the repulsive interactions between atoms [93, 94]. 

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 ... 

The second approach to dealing with poor data is the use of standard conformation libraries [3], It is clear that the use of perfect coordinates in such libraries to help building the model is to be preferred over coordinates with errors. However, there is one danger in the use of standard libraries circularity. Take, for example, side chain conformation libraries [3,18,19]. Residues positioned in a structure purely based on such a database will not easily be flagged as incorrect by rotamer... 

The course of the WHAT CHECK structural Z-scores throughout the past 10 years is depicted in Fig. 5. In this analysis, we determined several global Z-scores for all the structures solved in the past 10 years with a resolution between 1.8 and 2.2 A, by using the internal WHAT CHECK database generated in 2000. It can be seen from Fig. 5 that the chi-1/chi-2 rotamer distribution, in particular, has improved over the years, which is most likely due to the use of side-chain conformation libraries in structure determination. The other structural Z-scores show an insignificantly small... 

Correctly orientating side-chains Side-chain orientation is strongly dependent upon backbone conformation and local environmental featiues. Thus, the accuracy of side-chain placement in the model will depend upon the accuracy of the backbone. In general, in comparative modelling the most accurate placement of side-chains is achieved with the use of rotamer libraries (e.g. Lovell et al. Dunbrack and Karplus ). 

MD production runs are just a continuation of the MD equilibrium and continue up to several nanoseconds. The results from the production runs can be used for docking studies or to determine changes in the secondary or tertiary structure of the target protein. Protein models refined with MD simulations consist of a library of structures with similar backbone geometry, but with different side-chain rotamers. These different structures are especially useful for molecular docking studies when the conformation of the protein and the orientation of the side chains are unknown. 

---