A backbone-based theory of protein folding Export

@article{citeulike:935954, abstract = {10.1073/pnas.0606843103 Under physiological conditions, a protein undergoes a spontaneous disorder ⇌ order transition called ” folding.” The protein polymer is highly flexible when unfolded but adopts its unique native, three-dimensional structure when folded. Current experimental knowledge comes primarily from thermodynamic measurements in solution or the structures of individual molecules, elucidated by either x-ray crystallography or NMR spectroscopy. From the former, we know the enthalpy, entropy, and free energy differences between the folded and unfolded forms of hundreds of proteins under a variety of solvent/cosolvent conditions. From the latter, we know the structures of ≈35,000 proteins, which are built on scaffolds of hydrogen-bonded structural elements, α-helix and β-sheet. Anfinsen showed that the amino acid sequence alone is sufficient to determine a protein's structure, but the molecular mechanism responsible for self-assembly remains an open question, probably the most fundamental open question in biochemistry. This perspective is a hybrid: partly review, partly proposal. First, we summarize key ideas regarding protein folding developed over the past half-century and culminating in the current mindset. In this view, the energetics of side-chain interactions dominate the folding process, driving the chain to self-organize under folding conditions. Next, having taken stock, we propose an alternative model that inverts the prevailing side-chain/backbone paradigm. Here, the energetics of backbone hydrogen bonds dominate the folding process, with preorganization in the unfolded state. Then, under folding conditions, the resultant fold is selected from a limited repertoire of structural possibilities, each corresponding to a distinct hydrogen-bonded arrangement of α-helices and/or strands of β-sheet.}, address = {T. C. Jenkins Department of Biophysics,The Johns Hopkins University, Jenkins Hall, 3400 North Charles Street, Baltimore, MD 21218;}, author = {Rose, George D. and Fleming, Patrick J. and Banavar, Jayanth R. and Maritan, Amos}, citeulike-article-id = {935954}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0606843103}, citeulike-linkout-1 = {http://www.pnas.org/content/103/45/16623.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/103/45/16623.full.pdf}, citeulike-linkout-3 = {http://www.pnas.org/cgi/content/abstract/103/45/16623}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/17075053}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=17075053}, day = {7}, doi = {10.1073/pnas.0606843103}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences}, keywords = {folding, protein}, month = {November}, number = {45}, pages = {16623--16633}, posted-at = {2008-02-18 19:29:45}, priority = {2}, title = {A backbone-based theory of protein folding}, url = {http://dx.doi.org/10.1073/pnas.0606843103}, volume = {103}, year = {2006} }

TY - JOUR ID - citeulike:935954 L3 - citeulike-article-id:935954 N2 - 10.1073/pnas.0606843103 Under physiological conditions, a protein undergoes a spontaneous disorder ⇌ order transition called “folding.” The protein polymer is highly flexible when unfolded but adopts its unique native, three-dimensional structure when folded. Current experimental knowledge comes primarily from thermodynamic measurements in solution or the structures of individual molecules, elucidated by either x-ray crystallography or NMR spectroscopy. From the former, we know the enthalpy, entropy, and free energy differences between the folded and unfolded forms of hundreds of proteins under a variety of solvent/cosolvent conditions. From the latter, we know the structures of ≈35,000 proteins, which are built on scaffolds of hydrogen-bonded structural elements, α-helix and β-sheet. Anfinsen showed that the amino acid sequence alone is sufficient to determine a protein's structure, but the molecular mechanism responsible for self-assembly remains an open question, probably the most fundamental open question in biochemistry. This perspective is a hybrid: partly review, partly proposal. First, we summarize key ideas regarding protein folding developed over the past half-century and culminating in the current mindset. In this view, the energetics of side-chain interactions dominate the folding process, driving the chain to self-organize under folding conditions. Next, having taken stock, we propose an alternative model that inverts the prevailing side-chain/backbone paradigm. Here, the energetics of backbone hydrogen bonds dominate the folding process, with preorganization in the unfolded state. Then, under folding conditions, the resultant fold is selected from a limited repertoire of structural possibilities, each corresponding to a distinct hydrogen-bonded arrangement of α-helices and/or strands of β-sheet. IS - 45 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 AD - T. C. Jenkins Department of Biophysics,The Johns Hopkins University, Jenkins Hall, 3400 North Charles Street, Baltimore, MD 21218; EP - 16633 TI - A backbone-based theory of protein folding VL - 103 SP - 16623 KW - folding KW - protein AU - Rose, George AU - Fleming, Patrick AU - Banavar, Jayanth AU - Maritan, Amos PY - 2006/11/07/ UR - http://dx.doi.org/10.1073/pnas.0606843103 ER -