A critical assessment of comparative molecular modeling of tertiary structures of proteins*

Mosimann, S.C.; Meleshko, Ron; James, Michael N.G.

doi:10.1002/prot.340230305

Cited by 137 publications

(88 citation statements)

References 46 publications

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“…Because there is no spatial information provided from the template alignments, modeling the unaligned or loop regions is a hard, unsolved problem (3,38,39). Here, we define an unaligned or loop region (including tails) as a piece of continuous sequence that has no coordinate assignment in the SAL template alignments.…”

Section: Resultsmentioning

confidence: 99%

The protein structure prediction problem could be solved using the current PDB library

Zhang

Skolnick

2005

Proc. Natl. Acad. Sci. U.S.A.

274

215

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For single-domain proteins, we examine the completeness of the structures in the current Protein Data Bank (PDB) library for use in full-length model construction of unknown sequences. To address this issue, we employ a comprehensive benchmark set of 1,489 medium-size proteins that cover the PDB at the level of 35% sequence identity and identify templates by structure alignment. With homologous proteins excluded, we can always find similar folds to native with an average rms deviation (RMSD) from native of 2.5 Å with Ϸ82% alignment coverage. These template structures often contain a significant number of insertions͞deletions. The TASSER algorithm was applied to build full-length models, where continuous fragments are excised from the top-scoring templates and reassembled under the guide of an optimized force field, which includes consensus restraints taken from the templates and knowledge-based statistical potentials. For almost all targets (except for 2͞1,489), the resultant full-length models have an RMSD to native below 6 Å (97% of them below 4 Å). On average, the RMSD of full-length models is 2.25 Å, with aligned regions improved from 2.5 Å to 1.88 Å, comparable with the accuracy of low-resolution experimental structures. Furthermore, starting from state-of-theart structural alignments, we demonstrate a methodology that can consistently bring template-based alignments closer to native. These results are highly suggestive that the protein-folding problem can in principle be solved based on the current PDB library by developing efficient fold recognition algorithms that can recover such initial alignments. A s of December 30, 2003, Ͼ23,000 solved protein structures have been deposited in the Brookhaven Protein Data Bank (PDB) (1). This number keeps increasing, with Ϸ300 new entries added each month. The size and completeness of the PDB is essential to the success of template-based approaches to protein structure prediction. These methods include comparative modeling (2, 3) and threading (4-7), which are designed to infer an unknown sequence's structure based on solved, similarly folded protein structures in the PDB. Because an accurate theory for the prediction of protein structure on the basis of physical principles does not yet exist, comparative modeling͞threading approaches are the only reliable strategy for high-resolution tertiary structure prediction (8-10). On the other hand, the percentage of new folds in these new entries, the topology of which has never been seen in the current PDB library, keeps decreasing (e.g., the percentage of new folds was 27% in 1995 but 5% in 2001). The apparent saturation of new folds immediately raises an important question: At least for singledomain proteins, is the current structure library already complete enough to in principle solve the protein tertiary structure prediction problem at low-to-moderate resolutions?By means of a variety of structure comparison tools (11-14), this issue has been partially addressed by many authors (15)(16)(17)(18)(19)(20). It was demonstr...

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Section: Resultsmentioning

confidence: 99%

The protein structure prediction problem could be solved using the current PDB library

Zhang

Skolnick

2005

Proc. Natl. Acad. Sci. U.S.A.

274

215

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“…The modeling procedures have been described in detail elsewhere (32). Because of the high sequence similarity, the model was expected to be sufficiently reliable for prediction and analysis of the effects of most amino acid substitutions (32,33). This has been confirmed by the fact that the model has been used for the successful design of various stabilizing mutations (34 -37).…”

Section: Genetics-the Nprm Gene Encoding Tln Of Bacillus Thermoproteomentioning

confidence: 99%

Substrate Specificity in the Highly Heterogeneous M4 Peptidase Family Is Determined by a Small Subset of Amino Acids

Kreij

Venema

Burg³

2000

Journal of Biological Chemistry

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The members of the M4 peptidase family are involved in processes as diverse as pathogenicity and industrial applications. For the first time a number of M4 family members, also known as thermolysin-like proteases, has been characterized with an identical substrate set and a uniform set of assay conditions. Characterization with peptide substrates as well as high performance liquid chromatography analysis of ␤-casein digests shows that the M4 family is a homogeneous family in terms of catalysis, even though there is a significant degree of amino acid sequence variation. The results of this study show that differences in substrate specificity within the M4 family do not correlate with overall sequence differences but depend on a small number of identifiable amino acids. Indeed, molecular modeling followed by site-directed mutagenesis of one of the substrate binding pocket residues of the thermolysin-like proteases of Bacillus stearothermophilus converted the catalytic characteristics of this variant into that of thermolysin.

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“…Structure prediction by homology modelling has recently reached sufficient level of reliability [53,54] to allow close inspection of the psychrophilic enzyme conformation, keeping in mind the limit of confidence of such models. The active site of psychrophilic enzymes was subjected to careful examination.…”

Section: Reviews the Active Site Of Psychrophilic Enzymesmentioning

confidence: 99%

Psychrophilic enzymes: molecular basis of cold adaptation

Feller

Gerday

1997

CMLS, Cell. mol. life sci.

371

233

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Abstract. Psychrophilic organisms have successfully provides enhanced abilities to undergo conformational colonized polar and alpine regions and are able to grow changes during catalysis. Thermal instability of coldefficiently at sub-zero temperatures. At the enzymatic adapted enzymes is therefore regarded as a consequence level, such organisms have to cope with the reduction of of their conformational flexibility. A survey of the psychrophilic enzymes studied so far reveals only minor chemical reaction rates induced by low temperatures in alterations of the primary structure when compared to order to maintain adequate metabolic fluxes. Thermal compensation in cold-adapted enzymes is reached mesophilic or thermophilic homologues. However, all known structural factors and weak interactions inthrough improved turnover number and catalytic effivolved in protein stability are either reduced in number ciency. This optimization of the catalytic parameters can originate from a highly flexible structure which or modified in order to increase their flexibility.Key words. Psychrophiles; extremophiles; cold adaptation; microbial proteins; protein stability; weak interactions; Antarctic.Psychrophiles live at the lowest temperatures which allow the development of living organisms. These extremophilic organisms, either prokaryotic or eukaryotic, represent a major class of the living world if we consider the vast extent of permanently cold environments on Earth, such as polar and alpine regions or deep-sea waters. The successful colonization of such severe ecological niches by psychrophiles, their diversity and abundance are now well recognized. The lower temperature limit of life is commonly defined as the freezing point of cellular water. Although apparently simple by definition, this limit can drop significantly below 0°C, the freezing point of pure water. For instance, the freezing point of a typical marine teleost ranges between −0.5 and −0.9°C. Sodium chloride is responsible for about 85% of the freezing point depression, and the remaining 15% is due to other small solutes. Synthesis of antifreeze glycoproteins and peptides can further depress the freezing point of body fluids or cellular water. These proteins lower the freezing point by a noncolligative mechanism without altering the melting point significantly, and are therefore also referred to as thermal hysteresis proteins [1,2]. They were first discovered in the blood sera of Antarctic fish living perennially at about −1.9°C, but have been now reported in many organisms including plants, insects, fungi and bacteria [3][4][5]. Levels of thermal hysteresis activity generally range from 0.1 to 0.3°C in bacteria, from 0.2 to 0.5°C in plants, from 0.7 to 1.5°C in fish and from 3 to 6°C in insects. Besides the synthesis of cryoprotectants which lead to freeze avoidance, several organisms have developed mechanisms of freeze tolerance, involving drastic metabolic modifica-* Corresponding author.

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A critical assessment of comparative molecular modeling of tertiary structures of proteins*

Cited by 137 publications

References 46 publications

The protein structure prediction problem could be solved using the current PDB library

The protein structure prediction problem could be solved using the current PDB library

Substrate Specificity in the Highly Heterogeneous M4 Peptidase Family Is Determined by a Small Subset of Amino Acids

Psychrophilic enzymes: molecular basis of cold adaptation

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