![]() ![]() dG for this salt bridge has been calculated to be -22.4 kcal/mol. ![]() The side-chain ionised carboxylic acid oxygen atoms of Glu27 form two very strong hydrogen bonds with the side-chain protonated nitrogen atoms in the guanidinium group of Arg387, with the additional possibility of extra weaker cross h-bonds increasing stability. Whilst there is a significant desolvation penalty, the side chain centroids are 3.7 Angstroms apart, and the measured hydrogen bond length is only 1.94 Angstroms. One of the most stabilising salt bridges is formed by residues Glu27 and Arg387 in the human salivary a-amylase (PDB code: 1smd), shown in the image below. In general however as Fig 1 shows this is not a particularly common interaction, however charged functionality may improve physicochemical properties of the molecule. However in the case of salt bridges buried within the core of the protein there are many examples where they have been shown to be highly stabilising. Estimates for the strength of such interactions can be misleading since there is a large unfavourable desolvation term and for mobile residues on the surface of proteins there may be a significant entropic loss. In many cases a salt bridge is really a combination of hydrogen bonding and an ionic interaction. ![]() ![]() Kumar has shown that the 3D structure of many proteins is stabilised by internal salt bridges, many buried within the core of the protein. Salt Bridgesįor many biogenic amines a key requirement for ligand recognition is the interaction between a protonated amine in the ligand and a specific aspartic acid residue buried in the membrane domain of a GPCR. The most common interactions being hydrophobic, hydrogen bonds and pi-stacking. Desolvation plays a very important role, particularly with ionised or polar functional groups where there will be a large unfavourable desolvation term, in addition entropic changes can also have a significant influence.Ī detailed analysis of the molecular interactions present found between ligands and macromolecules has been undertaken, "A systematic analysis of atomic protein–ligand interactions in the PDB" DOI looking at over 11,000 complexes the authors were able to categorise the 7 most common types of interaction Fig 1. With many of these interactions simply looking at a model of a protein with a ligand docked can be misleading, only considering the bound state only gives part of the equation. Hence a small steric clash can cause the loss of all affinity. However it is important to note that steric clashes can have a much more pronounced impact on affinity, the interaction between two atoms is described by the Lennard-Jones potential shown graphically below.Īs you can see the attractive forces predominate when the atoms are further apart but when they get too close the repulsive forces become dramatically dominant. Since dG=-2.303RTlogK we can calculate that a single ionic interaction might afford a 25-fold increase in affinity, whilst a hydrogen bond yield a 6-fold increase, 3.5-fold increase in binding constant for a methyl group. Other have tried to estimate the strength of interaction by using chemical double mutants. Andrews has tried to estimate the average strength of various molecular interactions by examining the structural components and binding affinities of 200 compounds. Whilst the strength of a covalent single bond is usually in the region 80-100 Kcal/mol the non-covalent interactions exploited by medicinal chemists are much weaker. Whilst the overall physicochemical properties of the molecule can have a major influence it likely that specificity might be driven by optimisation of strength and geometry of specific molecular interactions. Much of medicinal chemistry is based on the optimisation or reduction of interactions between a small molecule and a variety of biomolecules, this can be increasing the affinity of a ligand for a receptor or reducing affinity for some undesired off-target interaction such as HERG or CYP450. ![]()
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