A backbone-based theory of protein folding

George D. Rose, Patrick J. Fleming, Jayanth R. Banavar, Amos Maritan

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)16623-16633
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - Nov 7 2006

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'A backbone-based theory of protein folding'. Together they form a unique fingerprint.

Cite this