Molecular protein-ligand

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. 

Bonaccorsi ct al. [204 defined for the first time the molecular electrostatic potential (MEP), wdicli is dearly tfie most important and most used property (Figure 2-125c. The clcctro.static potential helps to identify molecular regions that arc significant for the reactivity of compounds. Furthermore, the MEP is decisive for the formation of protein-ligand complexes. Detailed information is given in Ref [205]. 

I-J 1994. The Development of a Simple Empirical Scoring Fimction to Estimate the Binding istant for a Protein-ligand Complex of Known Three-Dimensional Structure. Journal of nputer-Aided Molecular Design 8 243-256. 

H-J 1998. Prediction of Binding Constants of Protein Ligands A Fast Method for the aritisation of Hits Obtained from De Novo Design or 3D Database Search Programs. Journal of nputer-Aided Molecular Design 12 309-323. 

I-J and G Klebe 1996. What Can We Learn From Molecular Recognition in Protein-Ligand nplexes for the Design of New Drugs Angewandte Chemie Iniemational Edition in English 2588-2614. 

Molecular recognition of protein-ligand complexes and drug design 97CRV1369. 

More detailed aspects of protein function can be obtained also by force-field based approaches. Whereas protein function requires protein dynamics, no experimental technique can observe it directly on an atomic scale, and motions have to be simulated by molecular dynamics (MD) simulations. Also free energy differences (e.g. between binding energies of different protein ligands) can be characterised by MD simulations. Molecular mechanics or molecular dynamics based approaches are also necessary for homology modelling and for structure refinement in X-ray crystallography and NMR structure determination. 

Bohm HI, Klebe G. What can we learn from molecular recognition in protein-ligand complexes for the design of new drugs Angew Chem Int Ed Engl 1996 35 2589-614. 

Babine RE, Bender SL. Molecular recognition of protein-ligand complexes applications to drug design. Chem Rev 1997 97 1359-472. 

Bohm HJ, Schneider G, editors. Protein-ligand interactions. From molecular recognition to drug design (Vol. 19 of Mannhold R, Kubinyi H, Foikers G, editors. Methods and Principles in Medicinal Chemistry). Weinheim Wiley-VCH, 2003. 

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