Predicting helical segments in proteins by a helix-coil transition theory with parameters derived from a structural database of proteins

Misra, Gauri P.; Wong, Chung F.

doi:10.1002/(sici)1097-0134(199707)28:3<344::aid-prot5>3.0.co;2-c

Cited by 12 publications

(1 citation statement)

References 49 publications

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“…This general approach has applications to a wide variety of problems in bioinformatics and biophysics. Our approach may be applied directly to the problem of protein secondary structure prediction using helix-coil models (Froimowitz and Fasman, 1974;Qian, 1996;Misra and Wong, 1997), with little modification. Of broader interest may be problems in empirical forcefield parameterization for protein structure prediction by threading and homology modeling, fragment reconstruction, and empirical energy minimization, as well as problems in protein-protein and protein-ligand docking.…”

Section: Resultsmentioning

confidence: 99%

Statistical Estimation of Statistical Mechanical Models: Helix-Coil Theory and Peptide Helicity Prediction

Schmidler

Lucas²,

Oas³

2007

Journal of Computational Biology

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Analysis of biopolymer sequences and structures generally adopts one of two approaches: use of detailed biophysical theoretical models of the system with experimentally-determined parameters, or largely empirical statistical models obtained by extracting parameters from large datasets. In this work, we demonstrate a merger of these two approaches using Bayesian statistics. We adopt a common biophysical model for local protein folding and peptide configuration, the helix-coil model. The parameters of this model are estimated by statistical fitting to a large dataset, using prior distributions based on experimental data. L(1)-norm shrinkage priors are applied to induce sparsity among the estimated parameters, resulting in a significantly simplified model. Formal statistical procedures for evaluating support in the data for previously proposed model extensions are presented. We demonstrate the advantages of this approach including improved prediction accuracy and quantification of prediction uncertainty, and discuss opportunities for statistical design of experiments. Our approach yields a 39% improvement in mean-squared predictive error over the current best algorithm for this problem. In the process we also provide an efficient recursive algorithm for exact calculation of ensemble helicity including sidechain interactions, and derive an explicit relation between homo- and heteropolymer helix-coil theories and Markov chains and (non-standard) hidden Markov models respectively, which has not appeared in the literature previously.

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Section: Resultsmentioning

confidence: 99%

Statistical Estimation of Statistical Mechanical Models: Helix-Coil Theory and Peptide Helicity Prediction

Schmidler

Lucas²,

Oas³

2007

Journal of Computational Biology

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Hydrogen bonds between short polar side chains and peptide backbone: Prevalence in proteins and effects on helix-forming propensities

1999

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A survey of 322 proteins showed that the short polar (SP) side chains of four residues, Thr, Ser, Asp, and Asn, have a very strong tendency to form hydrogen bonds with neighboring backbone amides. Specifically, 32% of Thr, 29% of Ser, 26% of Asp, and 19% of Asn engage in such hydrogen bonds. When an SP residue caps the N terminal of a helix, the contribution to helix stability by a hydrogen bond with the amide of the N3 or N2 residue is well established. When an SP residue is in the middle of a helix, the side chain is unlikely to form hydrogen bonds with neighboring backbone amides for steric and geometric reasons. In essence the SP side chain competes with the backbone carbonyl for the same hydrogen-bonding partner (i.e., the backbone amide) and thus SP residues tend to break backbone carbonyl-amide hydrogen bonds. The proposition that this is the origin for the low propensities of SP residues in the middle of alpha helices (relative to those of nonpolar residues) was tested. The combined effects of restricting side-chain rotamer conformations (documented by Creamer and Rose, Proc Acad Sci USA, 1992;89:5937-5941; Proteins, 1994;19:85-97) and excluding side- chain to backbone hydrogen bonds by the helix were quantitatively analyzed. These were found to correlate strongly with four experimentally determined scales of helix-forming propensities. The correlation coefficients ranged from 0.72 to 0.87, which are comparable to those found for nonpolar residues (for which only the loss of side-chain conformational entropy needs to be considered).

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Structural cassette mutagenesis in a de novo designed protein: Proof of a novel concept for examining protein folding and stability

et al. 1998

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The solution to the protein folding problem lies in defining the relative energetic contributions of short‐range and long‐range interactions. In other words, the tendency of a stretch of amino acids to adopt a final secondary structural fold is context dependent. Our approach to this problem is to address whether an amino acid sequence, a “cassette,” with a defined secondary structure in the three‐dimensional structure of a native protein, can adopt a different conformation when placed into a different protein environment. Thus, we designed de novo a disulfide‐bridged two‐stranded α‐helical parallel coiled coil, where each polypeptide chain consisted of 39 residues, as a “cassette holder.” The 11‐residue cassette would be inserted into the center of each polypeptide chain between the two nucleating α‐helices to replace the control sequence. This Structural Cassette Mutagenesis model permits the analysis of short‐range interactions within the inserted cassette as well as long‐range interactions between the nucleating helices and the cassette region. The cassette holder, with a control sequence as the cassette, had a GdnHCl transition midpoint during denaturation of 5.6M. To demonstrate the feasibility of our model, an 11‐residue β‐strand cassette from an immunoglobulin fold was inserted. The cassette was fully induced into the α‐helical conformation with a [GdnHCl]1/2 value of 3.2M. To demonstrate the importance of short‐range interactions (β‐sheet/α‐helical propensities of amino acid side chains) in modulating structure and stability, a series of 1–5 threonine residues (highest β‐sheet propensity) were substituted into the solvent‐exposed portions of the cassette in the α‐helical conformation. Each successive substitution systematically decreased the stability of the coiled coil with peptide T4b (4 Thr residues) having a [GdnHCl]1/2 value of 2.2M. The single substitution of Ile in the hydrophobic core of the cassette with Ala or Thr had the most dramatic effect on protein stability (peptide I20T, [GdnHCl]1/2 value of 1.4M). Though these substitutions were able to modulate stability, they were not able to disrupt the α‐helical conformation of the cassette, showing the importance of the nucleating α‐helices on either side of the cassette in controlling conformation of the cassette. We have demonstrated the feasibility of our model protein to accept a β‐strand cassette. The effect of cassettes containing other β‐strands, β‐turns, loops, regions of undefined structure, and helical segments on conformation and stability of our model protein will also be determined. © 1998 John Wiley & Sons, Inc. Biopoly 47: 101–123, 1998

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Predicting helical segments in proteins by a helix-coil transition theory with parameters derived from a structural database of proteins

Cited by 12 publications

References 49 publications

Statistical Estimation of Statistical Mechanical Models: Helix-Coil Theory and Peptide Helicity Prediction

Statistical Estimation of Statistical Mechanical Models: Helix-Coil Theory and Peptide Helicity Prediction

Hydrogen bonds between short polar side chains and peptide backbone: Prevalence in proteins and effects on helix-forming propensities

Structural cassette mutagenesis in a de novo designed protein: Proof of a novel concept for examining protein folding and stability

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