A backbone-based theory of protein folding

Abstract

Under physiological conditions, a protein undergoes a spontaneous disorder º 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 solvent͞cosolvent conditions. From the latter, we know the structures of Ϸ35,000 proteins, which are built on scaffolds of hydrogen-bonded structural elements, ␣-helix and ␤-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-chain͞backbone 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 ␣-helices and͞or strands of ␤-sheet.

Backbone additivity in the transfer model of protein solvation

“…11,12 This provides the basis of a universal mechanism for osmolyte-mediated protein stabilization by protecting osmolytes and destabilization by urea as the protein backbone is shared by all proteins, regardless of side chain sequence. [13][14][15] The evaluation of group transfer free energy values defined the now classic Tanford model for ureainduced protein denaturation. 16,17 In that model, the thermodynamic interaction of the side chains with the urea solution gave rise to the long held concept of favorable urea interaction with hydrophobic groups as a driving force in urea's denaturation effect.…”

On the satisfaction of backbone‐carbonyl lone pairs of electrons in protein structures

“…2,4,22 Our analysis is not at odds with this view, but we believe the picture is more detailed and subtle than often portrayed. Recently, others have demonstrated that, for the a-helix in particular, the classical model of NCIs may not always be appropriate.…”

“…21,22 In their hydrogen-bonding hypothesis, Fleming and Rose argue that all potential backbone hydrogen-bond donors and acceptors are satisfied a significant fraction of the time, either via intramolecular hydrogen bonds or hydrogen bonds to water. 23 The basis of the hypothesis is that unsatisfied hydrogen-bonding potential is highly unfavorable energetically and therefore rare.…”

Are amyloid fibrils molecular spandrels?

“…The fibrillization process is driven by protein backbone interactions; the protein backbone being a feature common to all proteins [26]. It is the hydrogen bonds within the backbone that drive this folding (or misfolding) process [27].…”