![]() The situation for transfer to a hydrophobic pocket on a protein surface is more complex as it may involve displacement of bound water molecules. This can be taken as an estimate of the possible gain for transfer of a solvent-exposed methyl group on a ligand into a hydrophobic region of a protein. In most cases, the benefit to Δ G tran is about 0.7 kcal/mol per added methyl group. The free energy of solvation in hexadecane becomes significantly more favorable with increasing methylation. Here, Δ G tran equals the difference in free energies of solvation in hexadecane, Δ G C16, and in water, Δ G hyd. The expected effects of methylation now become apparent as in the experimental data in Table 1 for transfer from aqueous to hexadecane solution. However, lipophilicity and the hydrophobic effect are taken to refer to transfer of a molecule from aqueous solution to a more lipid-like environment such as an alkane liquid, micelle, or interior of a protein. Thus, the gas/water partitioning of such molecules is normally affected little by addition of a methyl group or two. 16 For example, the first six entries show that Δ G hyd = −0.85 ± 0.05 kcal/mol for benzene and mono-, di- and tri-methylated analogs. 15a A similar pattern is seen upon methylation of aromatic molecules, as demonstrated by the experimental Δ G hyd values in Table 1. 15 However, for lower alkanes owing to enthalpy-entropy compensation, there is little variation in Δ G hyd, i.e., in the free energy of transfer from the gas phase to aqueous solution. 30 Å 2 and this increase, or the corresponding increase in number of water neighbors, scales linearly with free energies of hydration, Δ G hyd, for alkanes. The solvent-accessible surface area increases by ca. The typical view is that addition of a methyl group makes a molecule more hydrophobic and more prone to binding to biomolecules. ![]() 2– 6 Specifically, free energy perturbation (FEP) and thermodynamic integration (TI) methods with MC or MD sampling generally provide accurate predictions and have emerged as valuable in helping guide lead optimization. Among the many computational approaches that have been developed to study protein-ligand binding, free energy calculations in the context of Monte Carlo (MC) or molecular dynamics (MD) simulations are particularly powerful because they offer a rigorous way to compute binding affinities and relate thermodynamic quantities to molecular structures. To this end, molecular simulations have been carried out to gain detailed insights and to ascertain if the computations could reproduce the observations. Thus, we set out first to survey the literature for examples of the impact of methyl replacements on activity, and then to examine the most beneficial cases with available crystallographic data. However, apart from electrostatics and steric complementary between the ligand and its receptor, conformational energetics, desolvation and water placement in a binding site can also play important roles in the ligand binding process. One might envision a perfectly sized, hydrophobic pocket in a protein binding site ready to accept a methyl group. The present study began by wondering what would be the maximum improvement in biological activity that could be produced by such a change and what would be the structural circumstances leading to it. 1 Consistent with this, the most fundamental change in structure-activity studies is replacement of a hydrogen atom by a methyl group. ![]() ![]() The importance of methyl groups in modulating biological activity for small molecules is well documented. ![]()
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