Computational biochemistry ferenc Bogár György Ferency
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Note that the first two terms appear in the original LIE equation []. The first term represents the difference of the ligand-enzyme and ligand-water electrostatic interaction energies as calculated for the complex and for the solvated free ligand. The second term is similar for the van der Waals interaction energy. The last term includes the internal energies of the ligand in the bound and free states. The inclusion of this term was found to significantly improve the reproduction of experimental binding free energies. On the other hand, for the van der Waals term no multiplying factor different from 1 was found to improve the results. Experimental binding free energies were obtained from the measured ligand IC50 values (concentration causing 50% inhibition) with the formulas ΔG=RTlnKi and Ki=IC50/(1+S/Km) [], where Ki is the inhibition constant, S is the substrate concentration and Km is the Michaelis constant of the enzyme (see e.g. ref ). Calculated and experimental binding free energies are shown in Table 13.1 and Figure 13.12. below. Table 13.1. Experimental and calculated binding free energies and their components (kcal/mol) Adapted with permission from J. Med. Chem., 51, 7514–7522, (2008). Copyright 2008 American Chemical Society.
Figure 13.12. Calculated versus experimental binding free energies. The indicated line corresponds to perfect matching of the calculated and experimental values. Reprintedwith permission from J. Med. Chem., 51, 7514–7522, (2008). Copyright 2008 American Chemical Society. The mean unsigned error is 1.37 kcal/mol and this is remarkably good taking into account the simplicity of the model applied. A favorable van der Waals and an unfavorable electrostatic energy change accompanied binding for all molecules studied. The pro-pyrrolydine moiety adopts similar conformation in all complexes and this conformation is close to that observed in water. The conformational strain found to be significant for compounds with large N-terminal groups, namely for compounds 8, 10 and 11. Interestingly compound 9 has a lower conformational strain than does 8, although they have the same bulky N-terminal group. This can be rationalized by the longer alkyl chain of the former that gives more flexibility to the molecule. Further analysis of the binding modes and their energetic consequences can be found in ref. . 5. Summary In this chapter we gave examples of the application of some methods of biomolecular modelling on practical problems. Namely, molecular dynamics and a quantum chemical method were used for obtaining structural information for molecules with biological importance. 6. References J.W. Neidigh, R.M. Fesinmeyer, and N.H. AnderNat. Struct. Biol. 9, 425 (2002). K. Lindor-Larsen, S. Piana, K. Palmo, P. Maragakis, J.L. Klepeis, R.O. Dror, and D.E. Shaw. Proteins 78, 1950 (2010). W.L. Jorgensen, J. Chandrasekhar, J. Madura and M.L.Klein, J. Chem. Phys. 79, 926 (1983). B. Hess, C. Kutzner, D. van der Spoel, and E. Lindahl, J. Chem. Theory Comput. 4, 435 (2008); www.gromacs.org http://www.ks.uiuc.edu/Research/vmd/ J. Åqvist, C. Medina, J.–E. Samuelsson, “A new method for predicting binding affinity in computer-aided drug design”, Protein Eng., 7, 385-391, (1994). K. Kánai, P. Arányi, Z Böcskei, G. Ferenczy, V. Harmat, K. Simon, S. Bátori, G. Náray-Szabó, I. Hermecz “Prolyl Oligopeptidase Inhibition by N-Acyl-pro-pyrrolidine-type Molecules” J. Med. Chem., 51, 7514–7522, (2008). SYBYL Version 6.7, Tripos Inc., St. Louis, MO. Cheng, Y.-C.; Prusoff, W.H. “Relationship between inhibition constant (Ki) and the concentration of inhibition which causes 50% inhibition (IC50) of and enzyme reaction.” Biochem. Pharmacol. 22, 3099-3108, (1973). J.M. Berg, J.L. Tymoczko, L. Stryer “Biochemistry”, Freeman, New York, 2002. 7. Questions What is the meaning and mathematical definition of RMSD and RMSF? How can the more and less stable residues be identified using the RMSF values obtained from an MD trajectory? How is the symmetry of a molecule manifested on the different PES-s? What can we learn from the comparison of the absolute values of total energy at the different PES-s? How can we identify mathematically a minimum or saddle point on a PES? Please choose a stationary point from the presented PES-s and discuss the distinct structural properties of the corresponding molecular conformation (e.g. steric hindrance, staggered and eclipsed conformations of CH2 groups, etc.). 8. Glossary RMSD: Root-mean-squared-deviation RMSF: Root-mean-squared-fluctuation Created by XMLmind XSL-FO Converter. Directory: tartalom -> tamop412A tamop412A -> Agricultural Economics II. Popp, József Agricultural Economics II tamop412A -> Ethology practical Vilmos Altbäcker Márta Gácsi András Kosztolányi Ákos Pogány Gabriella Lakatos tamop412A -> Operating Systems Lecture Notes Attila Dr. Adamkó Operating Systems Lecture Notes tamop412A -> Agroinformatics Herdon, Miklós Agroinformatics tamop412A -> Paternoster of Programmers Reloaded tamop412A -> Lőrincz, András Mészáros, Tamás Pataki, Béla Embedded Intelligent Systems tamop412A -> This course is realized as a part of the TÁmop 1 A/1-11/1-2011-0038 project tamop412A -> Fundamentals of geology I. (lithosphere) 1 1. The formation of the Earth 1 Download 2.94 Mb. Share with your friends:
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