Peptide binding to MHC molecule

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Peptide binding to MHC molecule

Post by djm129129 » Sat Aug 23, 2008 2:59 pm

Hi everyone,
I have a certain peptide sitting in the binding groove of a class II MHC molecule. I need to mutate a serine residue to a tyrosine residue on the peptide and determine if the peptide can still bind to the MHC. I apologize for the ignorance as I am still learning, but as far as I can tell, as long as a residue is oriented into the binding pocket, it will still bind MHC as well as any of the potential residues still binding the peptide. Can one residue affect total binding?
Thanks for all your help, both past and present.

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Re: Peptide binding to MHC molecule

Post by blcr11 » Sun Aug 24, 2008 6:42 pm

A single substitution may affect binding, or it may not depending on the situation. Serine and tyrosine both have polar OH groups on their side chains, but tyrosine is much larger than serine (think of the difference in size between methanol and phenol and that’s about the right scale for comparison). If the serine fits the pocket well enough to make a hydrogen bond within the MHC peptide grove, it is likely that there won’t be enough room for a tyrosine side chain to occupy the same location and make the same kind of interaction. Assuming a rigid binding pocket (which may not always be the case either), it isn’t likely that tyrosine can substitute for serine especially if the serine is making an important contact with MHC.

Just imagining how a series of substitutions might go, substituting glycine for serine would be probably OK volume-wise (-H is smaller the -CH2OH) but doesn’t have the possibility for making a hydrogen bond; substituting cystine for serine also is OK sterically (-CH2SH is about the same size as -CH2OH and the sulfur is slightly polar) but sulfur doesn’t make as good a hydrogen bond as oxygen, so you would be seeing the effect of the strength of the H-bond potential. Substituting alanine for serine would be OK volume-wise, but the methyl side chain of alanine has no H-bonding potential compared to the -CH2OH of serine. And so on, you can continue to look at the nature of the side chain for each possible substitution and imagine how the size and chemistry of the side chain might either accept or interfere with the binding site relative to the way the site is occupied by serine.

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