Binding free energy calculation

So far 18 different members of HDACs have been discovered in humans and classified into four classes based on their homology to yeast histone deacetylases [33]. Class I includes four different subtypes (HDACl, 2, 3, 8), class II contains six subtypes tvhich are divided into two subclasses class Ila with subtypes HDAC4, 5, 7, 9 and class Ilb with HDAC6, 10. Class I and class II HDAC share significant structural homology, especially within the highly conserved catalytic domains. HDACs 6 and 10 are unique as they have two catalytic domains. HDACll is referred to as class IV. While the activity of class I, II and IV HDACs depends on a zinc based catalysis mechanism, the class III enzymes, also called sirtuins, require nicotinamide adenine dinucleotide as a cofactor for their catalysis. 

In the crystal structures, the inhibitors coordinate to the active site zinc and make a series of hydrogen bonds via their hydroxamic acid moiety. The hydroxamic acids are linked by a flexible spacer with bulky cap groups. The aromatic or aliphatic spacer participates in van der Waals interactions throughout the long charmel, whereas the terminal part of the inhibitor interacts with residues at the rim of HDAC. In general, the binding mode of the cocrystallized inhibitors TSA and SAHA is conserved among the different species and subtypes [35]. 

1 Docking Studies Using X-Ray Structures and Homology Models 

The published QSAR [59-61] and 3D-QSAR [62-65] models for HDAC inhibitors were used to explain the differences in activity of hydroxamate-based compounds. All the reported models, which showed moderate to good internal predictivity, were mainly used in a retrospectively way to explain the biological activities of H DAC inhibitors. Generally, the 3D-QSAR models were compared with ligand docking results to get insight into the structural requirements for anti-HDAC activity. 

the most probable protonation state of the reacting groups of the PTPase-substrate complex was determined using EVB and FEP techniques. 

Since concerted bond breaking and leaving group protonation was found to be considerably favored over a stepwise mechanism in the first part of the reaction, the analogous concerted pathway was also modeled here. Simulation of the first step showed that the protein environment cannot stabilize a negative ligand in the active site outside the phosphate binding loop, which would also be the case for a stepwise proton transfer to Asp 129 and a subsequent in-line attack of a hydroxide ion. 

Structure was solved. When Cysl7 was mutated to a serine the enzyme displayed low activity, but significant amounts of phosphoenzyme intermediate was trapped. This suggests that the larger thiol group better orients the water molecule than the smaller hydroxyl group in position 17. 

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The examples discussed here show that the new LIE parametrization of Ref. 26, while reliable for a number of systems, could not be the final word in the development of this type of approximate binding free energy calculations. As we will see below there may be more examples of ligand-receptor systems that don t fit the simple picture of Figure 1. 

M. D. Paulsen and R. L. Omstein, Binding free energy calculations for P450cam-... 

Figure 4. The free energy calculation results for all mutations. The numbers in italics are the relative binding free energies calculated from experimental Kj values. Other numbers are the relative binding free energies from the simulations. Units are kcal/mol.

Hou T, Wang J, Li Y, Wang W (2011) Assessing the performance of the MM/PBSA and MM/ GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J Chem Inf Model 51(l) 69-82... 

Solvation in Ligand Binding Free Energy Calculations Using the Generalized-Born Model. 

Verkhivker GM (2004) Computational analysis of ligand binding dynamics at the intermolecular hot spots with the aid of simulated tempering and binding free energy calculations, Mol J Graph Model, 22(5) 335-348... 

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Stjernschantz E, Marelius J, Medina C, Jacobsson M, Vermeulen NP, Oosten-brink C. Are automated molecular dynamics simulations and binding free energy calculations realistic tools in lead optimization An evaluation of the linear interaction energy (LIE) method. J Chem Inf Model 2006 46 1972-83. 

Wang, J., Deng, Y., and Roux, B. (2006) Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials. Biophys. J. 91, 2798-2814. 

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