Protein docking modeling

When the target protein of a small molecule is determined, it goes under validation with a number of biophysical, biochemical, and biological experiments, such as forward-affinity binding assay, reverse-affinity binding assay, small molecule-target protein docking model, surface plasmon resonance (SPR)... 

CAChe 5.0, available in 2002, includes a new, more powerful, semiempirical method that uses the PM5 Hamiltonian, a MOPAC 2002 offering, modeling of molecules with up to 20,000 atoms, the inclusion of all main group elements in one semiempirical method, and using MOPAC AMl-d, supports the transition metals Pt, Fe, Cu, Ag, Mo, V, and Pd. Researchers can now import and display, in 3D, proteins from the Protein Data Bank (PDB), optimize proteins, dock ligands, and model reactions on protein molecules. 

Benyamini, H., Gunasekaran, K., Wolfson, H., and Nussinov, R. (2003). Beta2-micro-globulin amyloidosis Insights from conservation analysis and fibril modelling by protein docking techniques./. Mol. Biol. 330, 159-174. 

Mizutani, M.Y., Tomioka, N., and Itai, A. Rational automatic search method for stable docking models of protein and ligand./. Mol. Biol. 1994, 243, 310-326. 

Xu M, Lill MA (2012) Utilizing experimental data for reducing ensemble size in flexible-protein docking. J Chem Inf Model 52(1) 187-198... 

V. Use of Molecular Models of Proteins Homology Models and Docking... 

V. USE OF MOLECULAR MODELS OF PROTEINS HOMOLOGY MODELS AND DOCKING... 

M. Y. Mizutani, N. Tomioka, and A. Itai,/. Mol. Biol., 243, 310 (1994). Rational Automatic Search Method for Stable Docking Models of Protein and Ligand. 

Gabb HA, Jackson RM, Sternberg MJE (1997) Modelling protein docking using shape complementarity, electrostatics and biochemical information. J Molecular Biology 272(1) 106—120... 

Sampling of the biomolecular conformations is usually performed using MD simulations or Monte Carlo methods (61, 62). The protonation state of titrateable amino acids can be treated with constant pH dynamics, QM/MM calculations, or continuum electrostatics methods (61, 62). Formation of a protein-protein encounter complex is often studied using Brownian dynamics (63). Studies of protein-protein docking involve electrostatic potential analysis and, more recently, protein flexibility models, for example normal mode analysis (64). 

Cherfils J, Duquerroy S, Janin J. Protein-protein recognition analyzed by docking simulation. Proteins 1991 11 271-280. Zacharias M. Protein-protein docking with a reduced protein model accounting for side chain flexibility. Protein Sci. 2354 12 1271-1282. 

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

The same method has been applied to measure the Eli domain orientation when the protein is in complex with its RNA parmer or both RNA and thiostrepton antibiotic. The additional RDCs revealed a rearrangement of the N-terminal domain of Ell placing it closer to the RNA after binding of thiostrepton. HADDOCK has been used to calculate a model of the ternary stmcture of the Ell protein in complex with RNA and antibiotic. Based on the orientational data, the dynamics and the docking model, it seems that thiostrepton locks the domain conformation of Ell in a rigid (inhibitory) state. The antibiotic thiostrepton interferes with the interaction of elongation factors to this Ell-RNA region, which has a dramatic effect on the level of protein synthesis by the ribosome. 

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