Modeling ligand complexes

To enable an atomic interpretation of the AFM experiments, we have developed a molecular dynamics technique to simulate these experiments [49], Prom such force simulations rupture models at atomic resolution were derived and checked by comparisons of the computed rupture forces with the experimental ones. In order to facilitate such checks, the simulations have been set up to resemble the AFM experiment in as many details as possible (Fig. 4, bottom) the protein-ligand complex was simulated in atomic detail starting from the crystal structure, water solvent was included within the simulation system to account for solvation effects, the protein was held in place by keeping its center of mass fixed (so that internal motions were not hindered), the cantilever was simulated by use of a harmonic spring potential and, finally, the simulated cantilever was connected to the particular atom of the ligand, to which in the AFM experiment the linker molecule was connected. 

Figure 10 Models of complexes between BLBP and two different fatty acids. The fatty acid ligand IS shown in the CPK representation. The small spheres in the ligand-bmdmg cavity are water molecules, (a) Model of the BLBP-oleic acid complex, in which the cavity is not filled, (b) Model of the BLBP-docosahexaenoic acid complex, m which the cavity is filled. The figure was prepared using the program MOLSCRIPT [236].

Keller, H. J., and Soos,-Z. G. Solid Charge-Transfer Complexes of Phenazines. 127, 169-216 (1985). Kellogg, R. M. Bioorganic Modelling — Stereoselective Reactions with Chiral Neutral Ligand Complexes as Model Systems for Enzyme Catalysis. 101, 111-145 (1982). 

The aim of the second dimension depth is to consider protein 3D-stmctures to uncover structure-function relationships. Starting from the protein sequences, the steps in the depth dimension are structure prediction, homology modeling of protein structures, and the simulation of protein-protein interactions and ligand-complexes. 

Bioorganic modelling. Stereoselective reactions with chiral neutral ligand complexes as model systems for enzyme catalysis. R. M. Kellogg, Top. Curr. Chem., 1982,101,111-145 (93). 

For many proteins, it is possible to generate structures of protein-ligand complexes quite rapidly. It is therefore not uncommon for many hundreds of structures to be determined in support of a drug discovery and optimization project. The major challenge for this level of throughput is informatics support. It is also this type of crystallography that is most in need of semiautomated procedures for structure solution and model building (see Section 12.6). 

Molecular modelling of opioid receptor-ligand complexes, 40 (2002) 107 Molecularly imprinted polymers,... 

Friesner RA (2006) Modeling polarization in proteins and protein-ligand complexes Methods and preliminary results. Adv Protein Chem 72 79-104... 

Kellogg, R. M. Bioorganic Modelling — Stereoselective Reactions with Chiral Neutral Ligand Complexes as Model Systems for Enzyme Catalysis. 101, 111-145 (1982). 

Pyridyl functionalized tris(pyrazolyl)borate ligands show some interesting properties including the formation of polynuclear zinc complexes.23,1 Some of these contain extensive H bonding and have potential as models for multinuclear zinc enzymes such as phospholipase C or PI nuclease.235 A bis-ligand complex of the hydrotris(5-methyl-3-(3-pyridyl)pyrazolyl)borate ligand (23) shows octahedral coordination of all six pyrazole nitrogen donors despite the steric bulk. 

Complexation, or chelation, is the process by which metal ions and organic or other non-metallic molecules (called ligands) can combine to form stable metal-ligand complexes. The complex that is found will generally prevent the metal from undergoing other reactions or interactions that the free metal cation would. Complexation may be important in some situations however, the current level of understanding of the process is not very advanced, and the available information has not been shown to be particularly useful to quantitative modeling (5). 

HGnn, J. Maigret, B. Tarek, M. Escrieut, C. Fourmy, D. Chipot, C., Probing a model of a GPCR/ligand complex in an explicit membrane environment. The human cholecystokinin-1 receptor, Biophys. J. 2006, 90, 1232-1240. 

Molecular simulation methods can be a complement to surface complexation modeling on metal-bacteria adsorption reactions, which provides a more detailed and atomistic information of how metal cations interact with specific functional groups within bacterial cell wall. Johnson et al., (2006) applied molecular dynamics (MD) simulations to analyze equilibrium structures, coordination bond distances of metal-ligand complexes. 

Figure I. Calculated vs. observed free energies of binding for the 18 receptor-ligand complexes used to derived the LIE model in Ref. 26.

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