Simple models of protein folding and of non-conventional drug design

R. A. Broglia, G. Tiana, D. Provasi

Research output: Contribution to journalReview articlepeer-review

18 Scopus citations

Abstract

While all the information required for the folding of a protein is contained in its amino acid sequence, one has not yet learned how to extract this information in order to predict the three-dimensional, biologically active, native conformation of a protein whose sequence is known. Using insights obtained from simple model simulations of the folding of proteins, in particular the fact that this phenomenon is essentially controlled by conserved (native) contacts among (few) strongly interacting ('hot'), as a rule hydrophobic, amino acids, which also stabilize local elementary structures (LES, hidden, incipient secondary structures such as α-helices and β-sheets) formed early in the folding process and leading to the postcritical folding nucleus (i.e. the minimum set of native contacts which brings the system beyond the highest free-energy barrier found in the whole folding process) it is possible to work out a successful strategy for reading the native structure of designed proteins from a knowledge of only their amino acid Sequence and of the contact energies among the amino acids. Because LES have undergone millions of years of evolution to selectively dock to their complementary structures, small peptides made out of the same amino acids as the LES are expected to selectively attach to the newly expressed (unfolded) protein and inhibit its folding, or to the native (fluctuating) native conformation and denature it. These peptides, or their mimetic molecules can thus be used as effective non-conventional drugs to those already existing (and directed at neutralizing the active site of enzymes), displaying the advantage of not suffering from the increase in resistance.

Original languageEnglish
Pages (from-to)R111-R144
JournalJournal of Physics Condensed Matter
Volume16
Issue number6
DOIs
StatePublished - 18 Feb 2004
Externally publishedYes

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