The Origins of Protein Secondary Structure

Hunt, Nathaniel; Gregoret, Lydia M.; Cohen, Fred E.

doi:10.1006/jmbi.1994.1490

Cited by 55 publications

(17 citation statements)

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“…Nevertheless, hydrogen bonding does play an important role in protein folding since highly polar sequences can fold to form -helices, and “side-chain only” molecular dynamics simulations fail to capture crucial aspects of protein folding [24]. Indeed, protein folding simulations have shown that it is necessary to include a mainchain-mainchain hydrogen bonding term in order to obtain secondary structure [25].…”

Section: Resultsmentioning

confidence: 99%

Inversion of the Balance between Hydrophobic and Hydrogen Bonding Interactions in Protein Folding and Aggregation

et al. 2011

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Identifying the forces that drive proteins to misfold and aggregate, rather than to fold into their functional states, is fundamental to our understanding of living systems and to our ability to combat protein deposition disorders such as Alzheimer's disease and the spongiform encephalopathies. We report here the finding that the balance between hydrophobic and hydrogen bonding interactions is different for proteins in the processes of folding to their native states and misfolding to the alternative amyloid structures. We find that the minima of the protein free energy landscape for folding and misfolding tend to be respectively dominated by hydrophobic and by hydrogen bonding interactions. These results characterise the nature of the interactions that determine the competition between folding and misfolding of proteins by revealing that the stability of native proteins is primarily determined by hydrophobic interactions between side-chains, while the stability of amyloid fibrils depends more on backbone intermolecular hydrogen bonding interactions.

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Section: Resultsmentioning

confidence: 99%

Inversion of the Balance between Hydrophobic and Hydrogen Bonding Interactions in Protein Folding and Aggregation

et al. 2011

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“…The chirality is defined as the sign of (r ជ i,iϩ1 ϫ r ជ iϩ1,iϩ2 )⅐r ជ iϩ2,iϩ3 . Our approach for the derivation of the geometrical constraints imposed by hydrogen bonds is similar to that carried out at the level of an all-atom description of the protein chain (37). For the simpler C ␣ atom-based description, hydrogen bond energy functions have been introduced previously (38, 39) but without any input from a statistical analysis of protein structures.…”

Section: Methodsmentioning

confidence: 99%

Geometry and symmetry presculpt the free-energy landscape of proteins

Hoang

Trovato²,

Seno³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

214

260

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We present a simple physical model that demonstrates that the native-state folds of proteins can emerge on the basis of considerations of geometry and symmetry. We show that the inherent anisotropy of a chain molecule, the geometrical and energetic constraints placed by the hydrogen bonds and sterics, and hydrophobicity are sufficient to yield a free-energy landscape with broad minima even for a homopolymer. These minima correspond to marginally compact structures comprising the menu of folds that proteins choose from to house their native states in. Our results provide a general framework for understanding the common characteristics of globular proteins. P rotein folding (1-5) is complex because of the sheer size of protein molecules, the twenty types of constituent amino acids with distinct side chains, and the essential role played by the environment. Nevertheless, proteins fold into a limited number (6, 7) of evolutionarily conserved structures (8, 9). It is a familiar, yet remarkable, consequence of symmetry and geometry that ordinary matter crystallizes in a limited number of distinct forms. Indeed, crystalline structures transcend the specifics of the various entities housed in them. Here, we ask the analogous question (10): is the menu of protein folds also determined by geometry and symmetry?We show that a simple model that encapsulates a few general attributes common to all polypeptide chains, such as steric constraints (11-13), hydrogen bonding (14-16), and hydrophobicity (17), gives rise to the emergent free-energy landscape of globular proteins. The relatively few minima in the resulting landscape correspond to putative marginally compact nativestate structures of proteins, which are assemblies of helices, hairpins, and planar sheets. A superior fit (18, 19) of a given protein or sequence of amino acids to one of these predetermined folds dictates the choice of the topology of its native-state structure. Instead of each sequence shaping its own free energy landscape, we find that the overarching principles of geometry and symmetry determine the menu of possible folds that the sequence can choose from.Following Bernal (20), the protein problem can be divided into two distinct steps: first, analogous to the elucidation of crystal structures, one must identify the essential features that account for the common characteristics of all proteins; second, one must understand what makes one protein different from another. Guided by recent work (21,22) that has shown that a faithful description of a chain molecule is a tube and using information from known protein native-state structures, our focus, in this paper, is on the first step: we demonstrate that the native-state folds of proteins emerge from considerations of symmetry and geometry within the context of a simple model.We model a protein as a chain of identical amino acids, represented by their C ␣ atoms, lying along the axis of a selfavoiding flexible tube.

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“…The appealing idea that helix formation is an early guiding event in protein folding (2-6) remains controversial (7)(8)(9)(10)(11). We suggest that the known facts are sufficient to resolve this controversy because they imply that side chain conformational entropy, and therefore helix propensity, must play an important organizing role during the earliest stages of protein folding.…”

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confidence: 89%