Geometry and symmetry presculpt the free-energy landscape of proteins

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We show that a framework derived from the common character of globular proteins can be used to understand the design of protein sequences, the behavior of intrinsically unstructured proteins, and the formation of amyloid fibrils in a unified manner. Our studies provide compelling support for the idea that protein native-state structures, the structures adopted by intrinsically unstructured proteins on binding as well as those of amyloid aggregates, all reside in a physical state of matter in which the free energy landscape is sculpted not by the specific sequence of amino acids, but rather by considerations of geometry and symmetry. We elucidate the key role played by sequence design in selecting the structure of choice from the predetermined menu of putative native-state structures.amyloid formation ͉ presculpted free energy landscape ͉ protein design ͉ protein folding I t is well known that the sequence of amino acids comprising a protein encodes its native-state structure. The protein folding problem, the determination of the native-state structure given a sequence of amino acids, however, has remained unsolved, in part because of the sheer complexity of the problem: the huge number of degrees of freedom associated with the protein atoms and the surrounding water molecules as well as the history dependence implicit in an evolutionary process. It was recently proposed (1, 2) that considerations of symmetry and geometry determine the limited menu of folded conformations from which a protein can choose for its native-state structure (3). Protein structures belong to a novel phase of matter associated with the marginally compact phase of short tubes with a thickness specially self-tuned to be comparable with the range of attractive interactions promoting the compaction. This phase is a finite size effect and exists only for relatively short tubes. That it is poised near a phase transition provides a simple explanation for the flexibility of native-state structures. The marginally compact phase is stabilized by the interplay of the hydrophobic (H) effect and hydrogen-bond formation. The structures that one finds in it are modular in construction, being made up of two principal building blocks, helices and planar sheets; the degeneracy is greatly reduced so that the number of the resulting energy minima is relatively small.The principal theme of our work is to present a unification of several seemingly distinct aspects of proteins within the unified framework sketched above, which is derived from the common characteristics of all proteins. We will tackle three issues: (i) protein design (4-12); (ii) intrinsically unstructured proteins (IUPs), which interact with different molecular partners and adopt relatively rigid conformations in the presence of natural ligands (13-19); and (iii) the propensity of proteins to misfold and aggregate leading to the formation of amyloid fibrils, which are implicated in debilitating human diseases (20-30) such as Alzheimer's, light-chain amyloidosis, type II diabetes, and spongiform...

Section: Resultscontrasting

confidence: 55%

Common attributes of native-state structures of proteins, disordered proteins, and amyloid

Hoang

Marsella

Trovato

et al. 2006

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“…Proteins are highly compact under folding conditions, with an average packing density resembling that of small organic solids (58). It has been shown that the conformational freedom of a compactly folded tube of polypeptide chain dimensions is severely limited by excluded volume restrictions in the marginally compact phase (47,59). Such chain organization is an automatic consequence of compact geometry and does not result in a glassy landscape.…”

Section: Universality Implies a Backbone-basedmentioning

confidence: 99%

“…Accordingly, it can be concluded that the free energy landscape is presculpted (47,48) into a few thousand intrinsically stable domains which are unmasked upon switching from unfolding to folding conditions. Specific sequences would be needed to discriminate among the possibilities in this repertoire, and exactly how this happens remains to be explained.…”

Section: Part 2 Questioning the Current Perspective: A Tale Of Two Lmentioning

confidence: 99%

A backbone-based theory of protein folding

Rose

Fleming

Banavar

et al. 2006

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456

412

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.

“…An alternative scheme would assume a single (or few) conformational property to be directly encoded in sequences, resulting in a small number of sequence-dependent parameters, whereas other conformational features would arise from sequence-independent constraints. The importance of such constraints has been recently emphasized by Banavar and collaborators (11).…”

mentioning

confidence: 99%

A sequence-compatible amount of native burial information is sufficient for determining the structure of small globular proteins

Araújo

Onuchic²

2009

Protein tertiary structures are known to be encoded in amino acid sequences, but the problem of structure prediction from sequence continues to be a challenge. With this question in mind, recent simulations have shown that atomic burials, as expressed by atom distances to the molecular geometrical center, are sufficiently informative for determining native conformations of small globular proteins. Here we use a simple computational experiment to estimate the amount of this required burial information and find it to be surprisingly small, actually comparable with the stringent limit imposed by sequence statistics. Atomic burials appear to satisfy, therefore, minimal requirements for a putative dominating property in the folding code because they provide an amount of information sufficiently large for structural determination but, at the same time, sufficiently small to be encodable in sequences. In a simple analogy with human communication, atomic burials could correspond to the actual "language" encoded in the amino acid "script" from which the complexity of native conformations is recovered during the folding process.protein folding | structure prediction | information theory | folding code D uring the last two decades, a physical picture of the folding process has emerged with the advent of energy landscape theory (1-5) but, despite many recent advances, a general solution to the problem of structure prediction from sequence has remained elusive. Most attempts in this direction have assumed sequences to encode partial information about many structural properties, such as likelihood of tertiary contacts or secondary structure propensities, that could eventually be combined to provide a general predictive algorithm (6-10). An alternative scheme would assume a single (or few) conformational property to be directly encoded in sequences, resulting in a small number of sequence-dependent parameters, whereas other conformational features would arise from sequence-independent constraints. The importance of such constraints has been recently emphasized by Banavar and collaborators (11).The amount of information provided by a putative single property dominating the code should satisfy two conditions: It should be sufficiently large for structural determination but sufficiently small for being encodable in sequences (12). The widely recognized importance of hydrophobic interactions on protein structure formation (13,14) suggests atomic burials to constitute a natural candidate for this putative dominant property. There has been some discussion, in the simplified context of lattice models, on the possibility that intrinsically unspecific hydrophobicity could satisfy the first condition (15), including a dependence on the choice of native conformation (16,17). Encouraging results from recent Monte Carlo simulations, on the other hand, indicate that the first condition is satisfied by atomic burials, as measured by distances from the molecular geometrical center, for small globular proteins represented by off-lattice, geome...