dorsal/arxiv
View SchemaSimple models of protein folding and of non--conventional drug design
| Authors | R. A. Broglia, G. Tiana |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0406031 |
| URL | https://arxiv.org/abs/q-bio/0406031 |
| DOI | 10.1088/0953-8984/16/6/R02 |
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 to predict the three--dimensional, biologically active, native conformation of a protein whose sequence is known. Using insight obtained from simple model simulations of the folding of proteins, in particular of 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 like $\alpha$--helices and $\beta$--sheets) formed early in the folding process and leading to the postcritical folding nucleus (i.e., the minimum set of native contacts which bring the system pass beyond the highest free--energy barrier found in the whole folding process) it is possible to work out a succesful strategy for reading the native structure of designed proteins from the 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 denaturate 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 uprise of resistance.
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"abstract": "While all the information required for the folding of a protein is contained\nin its amino acid sequence, one has not yet learned how to extract this\ninformation to predict the three--dimensional, biologically active, native\nconformation of a protein whose sequence is known. Using insight obtained from\nsimple model simulations of the folding of proteins, in particular of the fact\nthat this phenomenon is essentially controlled by conserved (native) contacts\namong (few) strongly interacting (\"hot\"), as a rule hydrophobic, amino acids,\nwhich also stabilize local elementary structures (LES, hidden, incipient\nsecondary structures like $\\alpha$--helices and $\\beta$--sheets) formed early\nin the folding process and leading to the postcritical folding nucleus (i.e.,\nthe minimum set of native contacts which bring the system pass beyond the\nhighest free--energy barrier found in the whole folding process) it is possible\nto work out a succesful strategy for reading the native structure of designed\nproteins from the knowledge of only their amino acid sequence and of the\ncontact energies among the amino acids. Because LES have undergone millions of\nyears of evolution to selectively dock to their complementary structures, small\npeptides made out of the same amino acids as the LES are expected to\nselectively attach to the newly expressed (unfolded) protein and inhibit its\nfolding, or to the native (fluctuating) native conformation and denaturate it.\nThese peptides, or their mimetic molecules, can thus be used as effective\nnon--conventional drugs to those already existing (and directed at neutralizing\nthe active site of enzymes), displaying the advantage of not suffering from the\nuprise of resistance.",
"arxiv_id": "q-bio/0406031",
"authors": [
"R. A. Broglia",
"G. Tiana"
],
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"q-bio.BM"
],
"doi": "10.1088/0953-8984/16/6/R02",
"title": "Simple models of protein folding and of non--conventional drug design",
"url": "https://arxiv.org/abs/q-bio/0406031"
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