Boltzmann's principle, knowledge-based mean fields and protein folding. An approach to the computational determination of protein structures

Sippl, Manfred J.

doi:10.1007/bf02337562

Cited by 365 publications

(326 citation statements)

References 43 publications

(51 reference statements)

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“…The structures were minimized by performing 4000 steps of steepest-descent minimization to resolve moderate and large energy conflicts. After minimization, the models were evaluated and compared with the template structures as well as unminimized models using WHAT IF version 4.99, PROCHECK version 3.5.4, and PROSA version 2.0 (45)(46)(47)(48)(49). Sequence similarity was calculated between NOS and the multiple sequences in the modeling alignment using PlotSimilarity from the Wisconsin Package version 9.0 software package (Genetics Computer Group) (50).…”

Section: Modelingmentioning

confidence: 99%

“…Plotted against the sequence is percentage of sequence conservation, in solid white representation, as calculated by the PlotSimilarity program from the GCG software package (50). PROSA was used to evaluate the structural quality of the reductase models, and the combined energy score is plotted as solid black circles for nNOS in panel A, eNOS in panel B, and iNOS in panel C. Desirable PROSA scores are low (45). The PROSA combined energy score was also calculated for the partial nNOS structure 1F20, and is shown as the trace of solid white squares in panel A.…”

Section: Figmentioning

confidence: 99%

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Nitric-oxide Synthase (NOS) Reductase Domain Models Suggest a New Control Element in Endothelial NOS That Attenuates Calmodulin-dependent Activity

Knudsen

Nishida

Mooney

et al. 2003

Journal of Biological Chemistry

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Inducible (iNOS) and constitutive (eNOS, nNOS) nitric-oxide synthases differ in their Ca2؉ -calmodulin (CaM) dependence. iNOS binds CaM irreversibly but eNOS and nNOS, which bind CaM reversibly, have inserts in their reductase domains that regulate electron transfer. These include the 43-45-amino acid autoinhibitory element (AI) that attenuates electron transfer in the absence of CaM, and the C-terminal 20 -40-amino acid tail that attenuates electron transfer in a CaMindependent manner. We constructed models of the reductase domains of the three NOS isoforms to predict the structural basis for CaM-dependent regulation. We have identified and characterized a loop (CD2A) within the NOS connecting domain that is highly conserved by isoform and that, like the AI element, is within direct interaction distance of the CaM binding region. The eNOS CD2A loop (eCD2A) has the sequence 834 KGSPG-GPPPG 843 , and is truncated to 809 ESGSY 813 (iCD2A) in iNOS. The eCD2A contributes to the Ca 2؉ dependence of CaM-bound activity to a level similar to that of the AI element. The eCD2A plays an autoinhibitory role in the control of NO, and CaM-dependent and -independent reductase activity, but this autoinhibitory function is masked by the dominant AI element. Finally, the iCD2A is involved in determining the salt dependence of NO activity at a post-flavin reduction level. Electrostatic interactions between the CD2A loop and the CaM-binding region, and CaM itself, provide a structural means for the CD2A to mediate CaM regulation of intra-subunit electron transfer within the active NOS complex.Nitric-oxide synthase (NOS), 1 a modular protein, consists of an N-terminal heme domain that catalyzes P450-like oxidations and a C-terminal two-flavin domain homologous to that of cytochrome P450 reductase (CPR) (1, 2). The NOS oxygenase and reductase domains are linked by a calmodulin (CaM) binding helix. The NOS oxygenase domain is completely different from a P450, however, in that it has no sequence identity with that family of enzymes and has an ␣,␤-fold structure distinct from the highly ␣-helical structure of the P450 enzymes (3-6). Furthermore, the two-stage mechanism for the oxidation of L-arginine to L-citrulline and nitric oxide (NO) by NOS is more complex than that of a P450 enzyme, as it requires tetrahydrobiopterin (H 4 B) as a transient electron donor (7). In contrast, the NOS reductase domain exhibits considerable sequence identity with CPR, and the electrons, as in P450/CPR, flow from NADPH to the FAD, then to the FMN, and finally, upon substrate binding, to the heme (2, 8).In the cytochrome P450 system, the principal control on inter-protein electron transfer is the requirement for association of the P450 with CPR. The NOS complex also requires interactions between independently transcribed proteins because it is a homodimer in which the reductase domain of one subunit provides electrons to the oxygenase domain of the other (9, 10). However, inter-domain electron transfer in NOS also requires the binding of CaM, and the Ca 2ϩ...

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Section: Modelingmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Nitric-oxide Synthase (NOS) Reductase Domain Models Suggest a New Control Element in Endothelial NOS That Attenuates Calmodulin-dependent Activity

Knudsen

Nishida

Mooney

et al. 2003

Journal of Biological Chemistry

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“…Because of this possibility the development of computational methods for automatic structure-structure comparison has received considerable recent attention [6]. For the same reason computational biologists are actively pursuing the development of 'threading' methods which attempt to detect similarity to a known structure given only the sequence of a newly discovered protein, and in the process to predict its tertiary structure [7,8,9,10,11,12,13].…”

Section: Introductionmentioning

confidence: 99%

Threading analysis suggests that the obese gene product may be a helical cytokine

1995

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The ob gene encodes a protein that, in mutant form, is associated with obesity and type II diabetes in mice. Sequence analysis has revealed no similarities to other proteins, however, and no clues as to possible functions. The possibility nonetheless remains that ob is functionally or ancestrally related to other proteins, whose sequences are divergent to the point that only a comparison of three-dimensional structures might detect relationship. To explore this possibility, we conduct a 'threading' search of a 3-dimensional structure database, to determine whether the ob protein might adopt a fold similar to any known structure. This search reveals that the ob sequence is compatible, at a significance level of P < 0.05, with structures from the family of helical cytokines that includes interleukin-2 and growth hormone. A structural model of ob based upon these results is physically and biologically plausible and leads to testable predictions, including the prediction that ob may activate the JAK-STAT pathway, via binding to a receptor resembling those of the cytokine family.

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“…global optimization ͉ thermodynamic hypothesis T o date, the great majority of successful algorithms for proteinstructure prediction are knowledge-based approaches; they make explicit use of homology modeling (1,2) or fold recognition methods (2)(3)(4)(5)(6). This feature even pertains to most of the methods considered as ab initio (7,8), which, in theory, should not make explicit use of structural databases.…”

mentioning

confidence: 99%

Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: Assessment in two blind tests

Ołdziej

Czaplewski

Liwo

et al. 2005

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

136

119

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Recent improvements in the protein-structure prediction method developed in our laboratory, based on the thermodynamic hypothesis, are described. The conformational space is searched extensively at the united-residue level by using our physics-based UNRES energy function and the conformational space annealing method of global optimization. The lowest-energy coarse-grained structures are then converted to an all-atom representation and energyminimized with the ECEPP͞3 force field. The procedure was assessed in two recent blind tests of protein-structure prediction. During the first blind test, we predicted large fragments of ␣ and ␣؉␤ proteins [60 -70 residues with C ␣ rms deviation (rmsd) <6 Å]. However, for ␣؉␤ proteins, significant topological errors occurred despite low rmsd values. In the second exercise, we predicted whole structures of five proteins (two ␣ and three ␣؉␤, with sizes of 53-235 residues) with remarkably good accuracy. In particular, for the genomic target TM0487 (a 102-residue ␣؉␤ protein from Thermotoga maritima), we predicted the complete, topologically correct structure with 7.3-Å C ␣ rmsd. So far this protein is the largest ␣؉␤ protein predicted based solely on the amino acid sequence and a physics-based potential-energy function and search procedure. For target T0198, a phosphate transport system regulator PhoU from T. maritima (a 235-residue mainly ␣-helical protein), we predicted the topology of the whole six-helix bundle correctly within 8 Å rmsd, except the 32 C-terminal residues, most of which form a ␤-hairpin. These and other examples described in this work demonstrate significant progress in physics-based protein-structure prediction.global optimization ͉ thermodynamic hypothesis T o date, the great majority of successful algorithms for proteinstructure prediction are knowledge-based approaches; they make explicit use of homology modeling (1, 2) or fold recognition methods (2-6). This feature even pertains to most of the methods considered as ab initio (7,8), which, in theory, should not make explicit use of structural databases. However, in-depth understanding of the physical principles of formation of protein structure requires the development of physics-based methods for proteinstructure prediction (9). Moreover, such methods will be independent of structural databases used in the training of knowledgebased methods. Furthermore, physics-based methods will enable us to study the structures of proteins that seem to possess a degenerate native state, such as the prion proteins, to simulate protein-folding pathways, to understand the mechanisms of protein folding, and to study interactions of proteins with other biomacromolecules and their assemblies (e.g., nucleic acids, polysaccharides, lipids, etc.). The underlying principle of physics-based methods for proteinstructure prediction is Anfinsen's thermodynamic hypothesis (10), according to which protein molecules adopt the conformations that are the global minima of their potential-energy surfaces. The methods based on this hypoth...

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Boltzmann's principle, knowledge-based mean fields and protein folding. An approach to the computational determination of protein structures

Cited by 365 publications

References 43 publications

Nitric-oxide Synthase (NOS) Reductase Domain Models Suggest a New Control Element in Endothelial NOS That Attenuates Calmodulin-dependent Activity

Nitric-oxide Synthase (NOS) Reductase Domain Models Suggest a New Control Element in Endothelial NOS That Attenuates Calmodulin-dependent Activity

Threading analysis suggests that the obese gene product may be a helical cytokine

Physics-based protein-structure prediction using a hierarchical protocol based on the UNRES force field: Assessment in two blind tests

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