Comparative Protein Structure Modeling of Genes and Genomes

Abstract

Comparative modeling predicts the three-dimensional structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. The number of protein sequences that can be modeled and the accuracy of the predictions are increasing steadily because of the growth in the number of known protein structures and because of the improvements in the modeling software. Further advances are necessary in recognizing weak sequence-structure similarities, aligning sequences with structures, modeling of rigid body shifts, distortions, loops and side chains, as well as detecting errors in a model. Despite these problems, it is currently possible to model with useful accuracy significant parts of approximately one third of all known protein sequences. The use of individual comparative models in biology is already rewarding and increasingly widespread. A major new challenge for comparative modeling is the integration of it with the torrents of data from genome sequencing projects as well as from functional and structural genomics. In particular, there is a need to develop an automated, rapid, robust, sensitive, and accurate comparative modeling pipeline applicable to whole genomes. Such large-scale modeling is likely to encourage new kinds of applications for the many resulting models, based on their large number and completeness at the level of the family, organism, or functional network.

Role of Substrate Positioning in the Catalytic Reaction of 4-Hydroxyphenylpyruvate Dioxygenase—A QM/MM Study

“…Ala1-Asp2-Leu3 and Asp357, were added with the program Modeller. [29][30][31][32] The ferrous ion was substituted with an iron-oxo group and acetate was replaced by HPA. Protonation states (at pH 7.0) of basic and acidic residues (other than iron ligands), were assigned based on pK a calculations performed with the PROPKA server, 33,34 with no unexpected protonation states predicted.…”

Evolution and Physics in Comparative Protein Structure Modeling

“…5 In this section, we list various comparative modeling approaches, errors in the resulting models, and their applications. We also point out the recent trends in large-scale comparative modeling of whole genomes and all known protein sequences.…”

“…1,5,22 Errors include mistakes in side-chain packing, relatively small shifts and distortions in correctly aligned regions, errors in the unaligned regions (i.e., loops), alignment errors, and fold assignment mistakes. The alignment errors increase rapidly below 30% sequence identity and become the most significant origin of errors in comparative models.…”

“…24 Reasonable applications of any protein structure model depend on its accuracy, and even models with large errors can be helpful. 4,5 Comparative models have been used in studying catalytic mechanisms of enzymes, designing and improving ligands, docking of macromolecules, predicting interacting protein partners, virtual screening and docking of small ligands, defining antibody epitopes, molecular replacement in X-ray crystallography, designing chimeras, stable and crystallizable variants, supporting site-directed mutagenesis, refining NMR structures, fitting proteins into low-resolution electron density maps, finding functional sites by 3D motif searching, determining structure from sparse experimental restraints, annotating function from structural relationships, and finding patches of conserved surface residues. 5 While the models can provide substantial insights, they can also be misleading.…”

Structure determination of symmetric homo‐oligomers by a complete search of symmetry configuration space, using NMR restraints and van der Waals packing

“…One can confidently predict protein interactions by homology modeling 6,7 only if the structure of a homologous complex is available. 8 Docking strategies usually involve a two-stage approach: generate a set of possible docked structures, and then score them. The possible structures are typically generated by sampling the space of rotations and translations of the docked subunit with respect to the fixed subunit.…”