Fold designability, distribution, and disease.
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ABSTRACT:
SUBMITTER: Wong P
PROVIDER: S-EPMC1456317 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A typical protein structure is a compact packing of connected alpha-helices and/or beta-strands. We have developed a method for generating the ensemble of compact structures a given set of helices and strands can form. The method is tested on structures composed of four alpha-helices connected by short turns. All such natural four-helix bundles that are connected by short turns seen in nature are reproduced to closer than 3.6 A per residue within the ensemble. Because structures with no natural counterpart may be targets for ab initio structure design, the designability of each structure in the ensemble-defined as the number of sequences with that structure as their lowest-energy state-is evaluated using a hydrophobic energy. For the case of four alpha-helices, a small set of highly designable structures emerges, most of which have an analog among the known four-helix fold families; however, several packings and topologies with no analogs in protein database are identified.
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Project description:The observation of a limited secondary-structural alphabet in native proteins, with significant sequence preferences, has profoundly influenced the fields of protein design and structure prediction (Simons, Kooperberg, Huang, & Baker, 1997; Verschueren et al., 2011). In the era of structural genomics, as the size of the structural dataset continues to grow rapidly, it is becoming possible to extend this analysis to tertiary structural motifs and their sequences. For a hypothetical tertiary motif, the rate of its utilization in natural proteins may be used to assess its designability-the ease with which the motif can be realized with natural amino acids. This requires a structural similarity search methodology, which rather than looking for global topological agreement (more appropriate for categorization of full proteins or domains), identifies detailed geometric matches. In this chapter, we introduce such a method, called MaDCaT, and demonstrate its use by assessing the designability landscapes of two tertiary structural motifs. We also show that such analysis can establish structure/sequence links by providing the sequence constraints necessary to encode designable motifs. As logical extension of their secondary-structure counterparts, tertiary structural preferences will likely prove extremely useful in de novo protein design and structure prediction.
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Project description:We recently found that many residues in enzyme active sites can be computationally predicted by the optimization of scoring functions based on substrate binding affinity, subject to constraints on the geometry of catalytic residues and protein stability. Here, we explore the generality of this surprising observation. First, the impact of hydrogen-bonding networks necessary for catalysis on the accuracy of sequence optimization is assessed; incorporation of these networks, where relevant, into the set of catalytic constraints is found to be essential. Next, the impact of multiple substrate selectivity on sequence optimization is probed by carrying out independent calculations for complexes of deoxyribonucleoside kinases with various cognate ligands, revealing how simultaneous selection pressures determined active-site sequences of these enzymes. Including previous calculations on simpler enzymes, computational sequence optimization correctly predicts 76% of all active-site residues tested (86% correct, with 93% similar, for naturally conserved residues). In these studies, the ligand is fixed in its native conformation. To assess the applicability of these methods to de novo active-site design, the effect of small ligand motions around the native pose is also examined. Robustness of sequence accuracy for topologically similar poses is demonstrated for selected kinases, but not for a model peptidase. Based on these observations, we introduce the notion of the designability of an enzyme active site, a metric that may be used to guide the search for protein scaffolds suitable for the introduction of de novo activity for a desired chemical reaction.
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Project description:Because the space of folded protein structures is highly degenerate, with recurring secondary and tertiary motifs, methods for representing protein structure in terms of collective physically relevant coordinates are of great interest. By collapsing structural diversity to a handful of parameters, such methods can be used to delineate the space of designable structures (i.e., conformations that can be stabilized with a large number of sequences)-a crucial task for de novo protein design. We first demonstrate this on natural α-helical coiled coils using the Crick parameterization. We show that over 95% of known coiled-coil structures are within 1-Å C(α) root mean square deviation of a Crick-ideal backbone. Derived parameters show that natural geometric space of coiled coils is highly restricted and can be represented by "allowed" conformations amidst a potential continuum of conformers. Allowed structures have (1) restricted axial offsets between helices, which differ starkly between parallel and anti-parallel structures; (2) preferred superhelical radii, which depend linearly on the oligomerization state; (3) pronounced radius-dependent a- and d-position amino acid propensities; and (4) discrete angles of rotation of helices about their axes, which are surprisingly independent of oligomerization state or orientation. In all, we estimate the space of designable coiled-coil structures to be reduced at least 160-fold relative to the space of geometrically feasible structures. To extend the benefits of structural parameterization to other systems, we developed a general mathematical framework for parameterizing arbitrary helical structures, which reduces to the Crick parameterization as a special case. The method is successfully validated on a set of non-coiled-coil helical bundles, frequent in channels and transporter proteins, which show significant helix bending but not supercoiling. Programs for coiled-coil parameter fitting and structure generation are provided via a web interface at http://www.gevorggrigoryan.com/cccp/, and code for generalized helical parameterization is available upon request.
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Project description:Background In discrete-choice experiments (DCEs), choice alternatives are described by attributes. The importance of each attribute can be quantified by analyzing respondents' choices. Estimates are valid only if alternatives are defined comprehensively, but choice tasks can become too difficult for respondents if too many attributes are included. Several solutions for this dilemma have been proposed, but these have practical or theoretical drawbacks and cannot be applied in all settings. The objective of the current article is to demonstrate an alternative solution, the fold-in, fold-out approach (FiFo). We use a motivating example, the ABC Index for burden of disease in chronic obstructive pulmonary disease (COPD). Methods Under FiFo, all attributes are part of all choice sets, but they are grouped into domains. These are either folded in (all attributes have the same level) or folded out (levels may differ). FiFo was applied to the valuation of the ABC Index, which included 15 attributes. The data were analyzed in Bayesian mixed logit regression, with additional parameters to account for increased complexity in folded-out questionnaires and potential differences in weight due to the folding status of domains. As a comparison, a model without the additional parameters was estimated. Results Folding out domains led to increased choice complexity for respondents. It also gave domains more weight than when it was folded in. The more complex regression model had a better fit to the data than the simpler model. Not accounting for choice complexity in the models resulted in a substantially different ABC Index. Conclusion Using a combination of folded-in and folded-out attributes is a feasible approach for conducting DCEs with many attributes.
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Project description:Highly designable structures can be distinguished based on certain geometric graphical features of the interactions, confirming the fact that the topology of a protein structure and its residue-residue interaction network are important determinants of its designability. The most designable structures and least designable structures obtained for sets of proteins having the same number of residues are compared. It is shown that the most designable structures predicted by the graph features of the contact diagrams are more densely packed, whereas the poorly designable structures are more open structures or structures that are loosely packed. Interestingly enough, it can also be seen that the highly designable identified are also common structural motifs found in nature.
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Project description:Heteropolymers are important examples of self-assembling systems. However, in the design of artificial heteropolymers the control over the single chain self-assembling properties does not reach that of the natural bio-polymers, and in particular proteins. Here, we introduce a sufficiency criterion to identify polymers that can be designed to adopt a predetermined structure and show that it is fulfilled by polymers made of monomers interacting through directional (anisotropic) interactions. The criterion is based on the appearance of a particular peak in the radial distribution function, that we show being a universal feature of all designable heteropolymers, as it is present also in natural proteins. Our criterion can be used to engineer new self-assembling modular polymers that will open new avenues for applications in materials science.
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