Side-chain modeling

Deciding how much of the template structure to remove before loop building depends on examination of the sequence alignment and the template structure. Sequence alignments with insertions and deletions are usually not unambiguous. Most sequence alignment methods ignorant of 

Loop structure prediction is always based in one way or another on an understanding of loop conformations in experimentally determined structures. Loop conformational analysis has been performed on a number of levels, ranging from classification of loops into a number of distinct types to statistical analysis of backbone dihedral angles. Loop classification schemes have usually been restricted to loops of a particular size range short loops of 1-4 residues, medium loops of 5-8 residues, and long loops of 9 residues or longer. 

Swindells et al. [120] have calculated the intrinsic j , i// propensities of the 20 amino acids from the coil regions of 85 protein structures. The distribution for coil regions is quite different than for the regular secondary structure regions, with a large increase in flP and oq conformations and much more diverse conformations in the pE and aR regions. Their results also indicate that the 18 non-Gly, Pro amino acid type are in fact quite different from each other in terms of their Ramachandran distributions, despite the fact that they are usually treated as identically distributed in prediction methods [95, 121]. Their analysis was divided into the main broad 

In recent years, as the size of the PDB has increased, database methods have continued to attract attention. With a larger database, recurring structural motifs have been classified for loop structures [111, 114, 116, 129, 134], including their sequence dependence. Database methods have been applied only for loops of up to 8 residues. Fidelis et al. [126] found that for loops of length greater than 7 there is not likely to be a segment in the PDB that corresponds to the correct loop conformations for the 58 protein they looked at. Some authors report that when the database contains a loop of similar structure to the target to be modeled, their methods perform well, with RMSD values around 1A or better. Otherwise they tend to fail [124, 127, 130]. 

Authors Availability Side chains Potential energy 

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Vasquez [121] reviewed and commented on various approaches to side chain modeling. The importance of two effects on side chain conformation was emphasized. The first effect was the coupling between the main chain and side chains, and the second effect was the continuous nature of the distributions of side chain dihedral angles for example. 

Terwilliger TC. Automated side-chain model building and sequence assignment by template matching. Acta Cryst 2003 D59 45-9. 

A step closer toward realism is taken by off-lattice models in which the backbone is specified in some detail, while side chains, if they are represented at all, are taken to be single, unified spheres [44-50]. One indication that this approach is too simplistic was given in [51], which proved that for a backbone representation in which only Ca carbons were modeled, no contact potential could stabilize the native conformation of a single protein against its nonnative ( decoy ) conformations. However, Irback and co-workers were able to fold real protein sequences, albeit short ones, using a detailed backbone representation, with coarse-grained side chains modeled as spheres [49, 52-54]. 

AA 1 Template Amino acid Side-chains Model TopoIoqy... 

FtA model hydrophobic-amphiphilic (side-chain) model ... 

One of the possible extensions of the HP model is the HA side chain model introduced in [212]. This is a more realistic coarse-grained model of amphiphilic polymers where the dualistic character of each monomeric unit is explicitly represented. 

Fig. 24 The side-chain models of amphiphilic polymers a amphiphilic homopolymer (poly-A), b regular alternating HA copolymer, c regular multiblock HA copolymer, and d protein-like HA copolymer. Each hydrophobic monomer unit (H) is considered as a single interaction site (bead) each amphiphilic group (A) is modeled by a dumbbell consisting of hydrophobic (H) and hydrophilic (P) beads...

Another method leading to nonaggregating copolymers may be connected with the molecular design of their monomeric units. We have discussed an extended variant of the HP model, the HA side-chain model [97], that explicitly takes into account the amphiphilic nature of hydrophilic segments. 

Wang C, Schueler-Furman O, Baker D. Improved side chain modeling for protein-protein docking. Protein Sci. 2005 14 1328-1339. 

K., Synthesis of retinals with eight- and nine-membered rings in the side chain. Models for rhodopsin photobleaching intermediates. J. Org. Chem., 58, 3533, 1993. 

This process is similar to the decision making crystallographers use to interpret electron density maps main-chain tracing followed by side-chain modeling. The used techniques take many of the constraints and criteria into account that a crystallographer would apply, and the created model can be refined by a crystallographer. 

Reduced side-chain model of Levitt CB-only in minimization of initial loops later bbdep rotamer library None... 

Samudrala and Moult described a method for handling context sensitivity of protein structure prediction, that is, simultaneous loop and side-chain modeling, using a graph theory method [198, 209] and an all-atom distance-dependent statistical potential energy function [199]. Their program RAMP is listed in Table 5.6. 

J. Mendes, C. M. Soares, M. A. Carrondo. Improvement of side-chain modeling in proteins with the self-consistent mean field theory method based on an analysis of the factors influencing prediction. Biopolymers. 1999, 50, 111-131. 

A A 24-methyl-25,26-dihydroxysteroidal side-chain was found in a highly polyhydroxysteroid (161) from the extracts of the New Caledonian starfish Arc/iasfer typicus (126). Simplified side-chain models were synthesized by epoxidation of ( )-2-methyl-2-pentenol followed by reaction with lithium dimethylcuprate to give the (2R,3R)/(2S,3S)-2, 3-dimethylpentane-1,2-diol enantiomeric pair (197a, b) (Fig. 22). This was converted into the (2S,3R)/(2R,3S)-enantiomeric pair (198a, b) by... 

Kokh, D.B. and Wenzel, W. (2008) Flexible side chain models improve enrichment rates in in silico screening. Journal of Medicinal Chemistry, 51, 5919-5931. 

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