What can disulfide bonds tell us about protein energetics, function and folding: simulations and bioninformatics analysis.
We study the impact of disulfide bonds on protein stability and folding. Using lattice model simulations, we show that formation of a disulfide bond stabilizes a protein to an extent that depends on the distance along the chain between linked cysteine residues. However, the impact of disulfide bonds on folding kinetics varies broadly, from acceleration when disulfides are introduced in or close to the folding nucleus, to slowing when disulfides are introduced outside the nucleus. Having established the effect of disulfide bonds on stability, we study the correlation between the number of disulfide bonds and the composition of certain amino acid classes with the goal to use it as a statistical probe into factors that contribute to stability of proteins. We find that the number of disulfides is negatively correlated with aliphatic hydrophobic but not aromatic content. It is surprising that we observe a strong correlation of disulfide content with polar (Q,S,T,N) amino acid content and a strong negative correlation with charged (E,D,K,R) content. These findings provide insights into factors that determine protein stability and principles of protein design as well as possible relations of disulfide bonds and protein function.
Abkevich
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Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
Shakhnovich
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EI
D000596:Amino Acids / Q000032:analysis; D019295:Computational Biology; D003198:Computer Simulation; D003545:Cysteine / Q000378:metabolism; D016208:Databases, Factual; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013223:Statistics as Topic; D013696:Temperature; D013816:Thermodynamics
D000596:Amino Acids; D004220:Disulfides; D011506:Proteins; D003545:Cysteine