Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain

ACS Medicinal Chemistry Letters
James M MyslinskiStephen F Martin

Abstract

Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and tripeptides of the general form Ac-pTyr-Xaa-Asn in which the Xaa residue bears a linear alkyl chain varying in length from 1-5 carbon atoms. Binding affinity increases upon adding a methylene group to the Ala derivative, but further chain extension gives no extra enhancement in potency. The thermodynamic signatures of the ethyl and n-propyl derivatives are virtually identical as are those for the n-butyl and n-pentyl analogs. Crystallographic analysis of the complexes reveals a high degree of similarity in the structure of the domain and the bound ligands with the notable exception that there is a gauche interaction in the side chains in the bound conformations of ligands having n-propyl, n-butyl, and n-pentyl groups. However, eliminating this unfavorable interaction by introducing a Z-double bond into the side chain of the n-propyl analog does not result in an increase in affinity. Increases in the amount of nonpolar surface that is buried upon ligand binding correlate with favorable changes in ΔH°, but these are usually offset by corresponding unfavorable changes in -TΔS°; there is little correlation of ΔC p with changes in the amou...Continue Reading

References

Jun 1, 1977·Proceedings of the National Academy of Sciences of the United States of America·J M Sturtevant
Dec 1, 1992·Protein Engineering·I TuñónJ L Pascual-Ahuir
Jan 1, 1988·Advances in Protein Chemistry·P L Privalov, S J Gill
Aug 10, 1999·Journal of Molecular Biology·S H SleighJ R Tame
Jun 23, 2001·Protein Science : a Publication of the Protein Society·V V LoladzeG I Makhatadze
Nov 7, 2002·Journal of the American Chemical Society·Bryce A HarrisonGregory L Verdine
Dec 5, 2002·Advances in Protein Chemistry·J Michael Bradshaw, Gabriel Waksman
Mar 21, 2003·Biophysical Chemistry·Jack Kyte
May 5, 2005·Annual Review of Biophysics and Biomolecular Structure·Ken A DillBarbara Hribar-Lee
Dec 1, 2005·Journal of the American Chemical Society·Richard MalhamSteve W Homans
Sep 27, 2006·Angewandte Chemie·Aaron P BenfieldStephen F Martin
Oct 22, 2008·Journal of Molecular Biology·Tjelvar S G OlssonJohn E Ladbury
Jul 11, 2009·Chemical Reviews·Huan-Xiang Zhou, Michael K Gilson
Oct 2, 2009·Chemical Biology & Drug Design·Ernesto Freire
Dec 5, 2009·Nature Reviews. Drug Discovery·John E LadburyErnesto Freire
Dec 24, 2009·Chemical Biology & Drug Design·Yuko KawasakiErnesto Freire
Sep 17, 2010·Journal of Chemical Theory and Computation·Piotr SetnyJ Andrew McCammon
Dec 1, 2010·ACS Medicinal Chemistry Letters·John E DelorbeStephen F Martin
Jul 9, 2011·Protein Science : a Publication of the Protein Society·Tjelvar S G OlssonMark A Williams
Jul 28, 2011·Journal of the American Chemical Society·Jasmin MecinovićGeorge M Whitesides
Oct 20, 2011·Journal of the American Chemical Society·James M MyslinskiStephen F Martin
Oct 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Phillip W SnyderGeorge M Whitesides
Jan 4, 2012·Journal of Computer-aided Molecular Design·Garland R Marshall
Jun 12, 2013·Annual Review of Biochemistry·Stephen F Martin, John H Clements
Jun 9, 2011·ACS Medicinal Chemistry Letters·Charles H Reynolds, M Katharine Holloway

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Citations

Jan 30, 2015·Angewandte Chemie·Elke PerschFrançois Diederich
Jul 25, 2017·The Journal of Organic Chemistry·Stephen F Martin

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