Side-chain optimization

L. Holm and C. Sander, Fast and simple Monte Carlo algorithm for side chain optimization in proteins. Proteins 14 (1992), 213-223. 

Schaffer, L. and Verkhivker, G. M. (1998) Predicting structural effects in HIV-1 protease mutant complexes with flexible ligand docking and protein side-chain optimization. Proteins Struct. Fund. Gen. 33,295-310. 

Two further energy functions based on Poisson-Boltzmann electrostatics and atomic solvation parameter (ASP)-based parameterizations of the solvation free energy changes43 were evaluated by Weng et al.57 in the context of side-chain optimization after rigid-body docking. 

To improve the efficiency of adjusting side chain rotamers, Schaffer and Verkhiv-ker implemented a postdocking side chain optimization procedure using the deadend elimination (DEE) algorithm, follo ved by local minimizations and energy evaluations of all generated DEE solutions [66]. 

The protein model on which the method is tested uses a three-atom per residue backbone and a one-atom side chain. " Optimization was carried out on melittin (26 residues), avian pancreatic polypeptide inhibitor (APPI) (36 residues), and apamin (18 residues). The fitness function used a molecular mechanics penalty as well as a penalty on the radius of gyration, which is a relatively straightforward value to obtain experimentally. In all three proteins, the GA found conformations of lower energy than that of the native structure, which was a problem with the force field, rather than with the optimization method. A standard SA method was also applied to this problem. It still found low-energy conformations, but took 100-200 times more function evaluations. 

Elworthy TR, Kertesz DJ, Kim W, Roepel MG, Quattrocchio-Setti L, Smith DB, Tracy JL, Chow A, Li F, Brill ER, Lach LK, McGee D, Yang DS, Chiou S-S (2004) Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1 2-pyrrolidinones - stereo-chemical and lower side-chain optimization. Bioorg Med Chem Lett 14 1655-1659... 

Another variation on this technique is to hrst optimize the side chains and then keep the side chains hxed while optimizing the backbone. In an extreme case, representing these hxed side chains as large polygons with some net interaction potential can increase the calculation speed even more. 

Use conventional conformation search techniques to optimize side chains. 

The rate of side-chain cleavage of sterols is limited by the low solubiUty of substrates and products and thek low transport rates to and from cells. Cyclodextrins have been used to increase the solubiUties of these compounds and to assist in thek cellular transport. Cyclodextrins increase the rate and selectivity of side-chain cleavage of both cholesterol and P-sitosterol with no effect on cell growth. Optimal conditions have resulted in enhancement of molar yields of androsta-l,4-diene-3,17-dione (92) from 35—40% to >80% in the presence of cyclodextrins (120,145,146,155). 

To understand the unpredictable nature of the Pictet-Gams reaction, Hartwig and Whaley conducted the first mechanistic studies in 1949. Their work focused on substituent effects when directly attached to the ethylamine side chain. They also investigated a variety of dehydration agents in order to identify optimal reaction conditions. It was determined that formation of the isoquinoline structure was virtually impossible when alkyl or phenyl substituents were placed in the 4-position of the ethylamine side chain. 

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. 

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