during discussion with relevence to enzyme active site we come to know that amino acids at active site have different pka as compared to when these amino acids present in free form if anybody had explanation ?or this is the fact to find out active site of enzyme
pKa is related to the side chain of the amino acid. This side chain can interact with other residues of the enzyme (hydrogen bonding and others) and this greatly affects the pKa value.
pKa is a measure of what proportion of the time an atom is protonated. When free in solution the amino acid is only affected by the solvent. However when in the active site the local environment will have a large effect. For instance an acidic residue may be in a hydrophobic environment which prevents it losing the proton and becoming charged. Alternatively it may be adjacent to a basic residue which readily removes the proton and stabilising the new charge. There are two examples of factors which can affect the pKa and so in a protein environment the pKa can be radically different than free in solution.
pKa of an amino acid which contains an amino group (a basic center that can be protonated and thus becomes possitively charged) and a carboxylic group (an acidic group that can donate a proton and becomes negatively charged). The binding site in an enzyme or a receptor is much favoured than the other plasma or cellular proteins because of the presence of suitable functional groups that strongly interact with the drug molecule. Thus, in the suitable binding site, almost all of the carboxylic groups are in their carboxylate feature, and all of the amino groups are protonated. Proton transfer is in between the drug molecule with the functional groups of the amino acids lining the binding site of action. I wrote almost, because each organ has its specific pH, e.g. Plasma is about 7.4, but kidney is less than 5
Dissociation of carboxylic groups within protein may require change in secondary or tertiary structure. These groups are thus much weaker acids than corresponding free amino acids.
I have a paper on that. It is available for free from the web page of FEBS Letters: https://febs.onlinelibrary.wiley.com/doi/full/10.1016/S0014-5793%2899%2901536-7
I think combined effects on several spatial scales should be considered. The pK can change due to molecular chemical changes (with which I mean the factors that cause the differences in acidity of different acids, but also the factors that cause the change in acidity of acetic acid as the protons in the methyl group are stepwise replaced by Cl) to electrostatic effects due to changes in structure inside macromolecules, allostery, and change in hydrophobic/hydrophilic character of the local environment. A holistic approach is needed in which all the factors mentioned above, and there may be others (temperature) , are quantitatively compared. Maybe this has already been done. Does anyone know such a study? If not, does anyone have some spare time?
The pK can change site due to molecular chemical changes (with which I mean the factors that cause the differences in acidity of different acids, but also the factors that cause the change in acidity of acetic acid as the protons in the methyl group are stepwise replaced by Cl) to electrostatic effects due to changes in site
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