The Protein Coil Library: A structural database of nonhelix, nonstrand fragments derived from the PDB

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Reconstructing a protein in three dimensions from its backbone torsion angles is an ongoing challenge because minor inaccuracies in these angles produce major errors in the structure. As a familiar example, a small change in an elbow angle causes a large displacement at the end of your arm, the longer the arm, the larger the displacement. Even accurate knowledge of the backbone torsions and is insufficient, owing to the small, but cumulative, deviations from ideality in backbone planarity, which, if ignored, also lead to major errors in the structure. Against this background, we conducted a computational experiment to assess whether protein conformation can be determined from highly approximate backbone torsion angles, the kind of information that is now obtained readily from NMR. Specifically, backbone torsion angles were taken from proteins of known structure and mapped into 60°؋ 60°grid squares, called mesostates. Side-chain atoms beyond the ␤-carbon were discarded. A mesostate representation of the protein backbone was then used to extract likely candidates from a fragment library of mesostate pentamers, followed by Monte Carlo-based fragment-assembly simulations to identify stable conformations compatible with the given mesostate sequence. Only three simple energy terms were used to gauge stability: molecular compaction, soft-sphere repulsion, and hydrogen bonding. For the six representative proteins described here, stable conformers can be partitioned into a remarkably small number of topologically distinct clusters. Among these, the native topology is found with high frequency and can be identified as the cluster with the most favorable energy.protein structure ͉ protein secondary structure ͉ protein fragment assembly ͉ Monte Carlo simulation P rotein molecules are known to undergo a reversible disorder order transition (1). In the classical view, the unfolded state is thought to be a structurally featureless ensemble that adopts its native structure spontaneously and uniquely under conditions that favor folding. For many small proteins of biophysical interest, this well studied folding reaction is apparently a two-state process. Accordingly, it can be represented by the equation: U(nfolded)^N(ative), with equilibrium constant, K eq ϭ N͞U, and free energy, ⌬G 0 ϭ ϪRT ln K eq , the free energy difference between the two populations. Central to this view, U is thought to be largely comprised of randomly coiled molecules, and N is thought to be largely comprised of uniquely structured molecules.Lately, we have been exploring the doubly divergent alternative view that the unfolded state is more organized (2) and the folded state is less homogeneous (3) than previously thought. If so, then both states can be treated productively as constrained thermodynamic ensembles. Numerous recent papers suggest that the unfolded population is not featureless, despite the fact that it does indeed exhibit random-coil statistics (4). Based on residual dipolar couplings from NMR, Shortle (5) and Shortle and Ackerman (6) have a...

mentioning

confidence: 89%

Building native protein conformation from highly approximate backbone torsion angles

Gong

Fleming

Rose

2005

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“…Other regions are predicted to be unpopulated because their backbone torsion angles would cause a steric clash within the dipeptide unit. , distributions of experimental data from the major populated regions from the coil library (88) are shown superimposed on the predicted sterically allowed regions.…”

Section: Part 1 Protein Folding: the Current Perspectivementioning

confidence: 99%

“…These isodirectional segments account for approximately half of protein structures on average (88), and incorporating them into a three-dimensional structure requires turns and loops that can reverse the overall chain direction. However, ␤-turns are hydrogen-bonded backbone elements too (44), and they comprise at least half of the remaining protein structure (89).…”

Section: What Anfinsen Could Not Have Knownmentioning

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.

“…However, quantitative differences in relative populations among the amino acid residues are evident. The "Coil Library" of residue conformations outside helices and sheets (3)(4)(5) also contains regions outside the three major basins and specific structures, minor in amounts, have been dissected (6).…”

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confidence: 99%

Populations of the three major backbone conformations in 19 amino acid dipeptides

Grdadolnik

Mohaček-Grošev

Baldwin

et al. 2011

111

202

The amide III region of the peptide infrared and Raman spectra has been used to determine the relative populations of the three major backbone conformations (P II , β, and α R ) in 19 amino acid dipeptides. The results provide a benchmark for force field or other methods of predicting backbone conformations in flexible peptides. There are three resolvable backbone bands in the amide III region. The major population is either P II or β for all dipeptides except Gly, whereas the α R population is measurable but always minor (≤10%) for 18 dipeptides. (The Gly φ,ψ map is complex and so is the interpretation of the amide III bands of Gly.) There are substantial differences in the relative β and P II populations among the 19 dipeptides. The band frequencies have been assigned as P II , 1,317-1,306 cm −1 ; α R , 1,304-1,294 cm −1 ; and β, 1,294-1,270 cm −1 . The three bands were measured by both attenuated total reflection spectroscopy and by Raman spectroscopy. Consistent results, both for band frequency and relative population, were obtained by both spectroscopic methods. The β and P II bands were assigned from the dependence of the 3 JðH N ,H α Þ coupling constant (known for all 19 dipeptides) on the relative β population. The P II band assignment agrees with one made earlier from Raman optical activity data. The temperature dependences of the relative β and P II populations fit the standard model with Boltzmann-weighted energies for alanine and leucine between 30 and 60°C.vibrational spectroscopy | backbone conformations | spectral populations | aqueous solution A basic unsolved problem in protein folding is making accurate calculations of the folding energetics of flexible peptides. Accurate experimental results for the major backbone conformations are needed to test prediction methods. Even the simple problem of calculating the φ,ψ map of the alanine dipeptide is beyond the reach of standard force fields used in molecular dynamics simulations (1). There are two probable reasons: one is that the energy differences between the major backbone conformations are small, and the second is that standard force fields contain so many parameters that errors cannot be found readily by comparing simulations with experimental results. The ability to calculate accurately the relative energies of the various backbone conformations is needed for simulating early stages of the protein folding process, which is an important current problem in molecular biophysics.When simulated by standard force fields, the φ,ψ map of the alanine dipeptide has three major conformational basins, P II , β, and α R . Different force fields agree on this point but give widely varying results for the populations in the three basins (1). The φ,ψ maps of the 19 amino acid residues (Pro excluded) from the protein structure database show the same three basins and are similar in outline for the various residues if data for Gly and Pre-Pro are excluded in addition to Pro (2). The three basins are centered approximately at P II (−75°, 145°), β (−120°, 120°), a...