@proceedings {Steczkiewicz2011, title = {Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {108}, number = {23}, year = {2011}, month = {jun}, pages = {9443{\textendash}8}, abstract = {Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the "end-replication" problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNADNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design.}, keywords = {Amino Acid, Amino Acid Sequence, Binding Sites, Binding Sites: genetics, Catalytic Domain, Computer Simulation, DNA, DNA: chemistry, DNA: genetics, DNA: metabolism, Humans, Kinetics, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Nucleic Acid Heteroduplexes, Nucleic Acid Heteroduplexes: chemistry, Nucleic Acid Heteroduplexes: genetics, Nucleic Acid Heteroduplexes: metabolism, Polymerization, Protein Binding, Protein Structure, RNA, RNA: chemistry, RNA: genetics, RNA: metabolism, Secondary, Sequence Homology, Telomerase, Telomerase: chemistry, Telomerase: genetics, Telomerase: metabolism, Telomere, Telomere: chemistry, Telomere: genetics, Telomere: metabolism, Tertiary}, issn = {1091-6490}, doi = {10.1073/pnas.1015399108}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3111281\&tool=pmcentrez\&rendertype=abstract}, author = {Kamil Steczkiewicz and Michael T. Zimmermann and Mateusz Kurcinski and Benjamin A. Lewis and Drena Dobbs and Andrzej Kloczkowski and Robert L. Jernigan and Andrzej Koli{\'n}ski and Krzysztof Ginalski} } @article {Gront2005a, title = {A new approach to prediction of short-range conformational propensities in proteins}, journal = {Bioinformatics (Oxford, England)}, volume = {21}, number = {7}, year = {2005}, pages = {981{\textendash}987}, abstract = {

MOTIVATION: Knowledge-based potentials are valuable tools for protein structure modeling and evaluation of the quality of the structure prediction obtained by a variety of methods. Potentials of such type could be significantly enhanced by a proper exploitation of the evolutionary information encoded in related protein sequences. The new potentials could be valuable components of threading algorithms, ab-initio protein structure prediction, comparative modeling and structure modeling based on fragmentary experimental data. RESULTS: A new potential for scoring local protein geometry is designed and evaluated. The approach is based on the similarity of short protein fragments measured by an alignment of their sequence profiles. Sequence specificity of the resulting energy function has been compared with the specificity of simpler potentials using gapless threading and the ability to predict specific geometry of protein fragments. Significant improvement in threading sensitivity and in the ability to generate sequence-specific protein-like conformations has been achieved.

}, keywords = {Algorithms, Amino Acid, Artificial Intelligence, Chemical, Computer Simulation, Databases, Gas Chromatography-Mass Spectrometry, Gas Chromatography-Mass Spectrometry: methods, Models, Protein, Protein Conformation, Protein: methods, Proteins, Proteins: analysis, Proteins: chemistry, Sequence Alignment, Sequence Alignment: methods, Sequence Analysis, Sequence Homology, Structure-Activity Relationship}, issn = {1367-4803}, doi = {10.1093/bioinformatics/bti080}, url = {http://www.ncbi.nlm.nih.gov/pubmed/15509604}, author = {Dominik Gront and Andrzej Koli{\'n}ski} } @article {Rotkiewicz2001, title = {Model of three-dimensional structure of vitamin D receptor and its binding mechanism with 1alpha,25-dihydroxyvitamin D(3)}, journal = {Proteins}, volume = {44}, number = {3}, year = {2001}, month = {2001}, pages = {188{\textendash}199}, abstract = {Comparative modeling of the vitamin D receptor three-dimensional structure and computational docking of 1alpha,25-dihydroxyvitamin D(3) into the putative binding pocket of the two deletion mutant receptors: (207-423) and (120-422, Delta [164-207]) are reported and evaluated in the context of extensive mutagenic analysis and crystal structure of holo hVDR deletion protein published recently. The obtained molecular model agrees well with the experimentally determined structure. Six different conformers of 1alpha,25-dihydroxyvitamin D(3) were used to study flexible docking to the receptor. On the basis of values of conformational energy of various complexes and their consistency with functional activity, it appears that 1alpha,25-dihydroxyvitamin D(3) binds the receptor in its 6-s-trans form. The two lowest energy complexes obtained from docking the hormone into the deletion protein (207-423) differ in conformation of ring A and orientation of the ligand molecule in the VDR pocket. 1alpha,25-Dihydroxyvitamin D(3) possessing the A-ring conformation with axially oriented 1alpha-hydroxy group binds receptor with its 25-hydroxy substituent oriented toward the center of the receptor cavity, whereas ligand possessing equatorial conformation of 1alpha-hydroxy enters the pocket with A ring directed inward. The latter conformation and orientation of the ligand is consistent with the crystal structure of hVDR deletion mutant (118-425, Delta [165-215]). The lattice model of rVDR (120-422, Delta [164-207]) shows excellent agreement with the crystal structure of the hVDR mutant. The complex obtained from docking the hormone into the receptor has lower energy than complexes for which homology modeling was used. Thus, a simple model of vitamin D receptor with the first two helices deleted can be potentially useful for designing a general structure of ligand, whereas the advanced lattice model is suitable for examining binding sites in the pocket.}, keywords = {Amino Acid, Amino Acid Sequence, Animals, Binding Sites, Calcitriol, Calcitriol: chemistry, Calcitriol: genetics, Computational Biology, Humans, Ligands, Models, Molecular, Molecular Sequence Data, Point Mutation, Protein Conformation, Protein Structure, Rats, Receptors, Sequence Homology, Tertiary}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/11455592}, author = {Piotr Rotkiewicz and Wanda Sicinska and Andrzej Koli{\'n}ski and Hector F. DeLuca} } @article {Hu1997, title = {Improved method for prediction of protein backbone U-turn positions and major secondary structural elements between U-turns}, journal = {Proteins}, volume = {29}, number = {4}, year = {1997}, pages = {443{\textendash}460}, abstract = {A new and more accurate method has been developed for predicting the backbone U-turn positions (where the chain reverses global direction) and the dominant secondary structure elements between U-turns in globular proteins. The current approach uses sequence-specific secondary structure propensities and multiple sequence information. The latter plays an important role in the enhanced success of this approach. Application to two sets (total 108) of small to medium-sized, single-domain proteins indicates that approximately 94\% of the U-turn locations are correctly predicted within three residues, as are 88\% of dominant secondary structure elements. These results are significantly better than our previous method (Kolinski et al., Proteins 27:290-308, 1997). The current study strongly suggests that the U-turn locations are primarily determined by local interactions. Furthermore, both global length constraints and local interactions contribute significantly to the determination of the secondary structure types between U-turns. Accurate U-turn predictions are crucial for accurate secondary structure predictions in the current method. Protein structure modeling, tertiary structure predictions, and possibly, fold recognition should benefit from the predicted structural data provided by this new method.}, keywords = {Amino Acid, Amino Acid Sequence, Amino Acids, Amino Acids: chemistry, Data Interpretation, Models, Molecular, Molecular Sequence Data, Protein Structure, Proteins, Proteins: chemistry, Reproducibility of Results, Secondary, Sequence Alignment, Sequence Alignment: methods, Sequence Alignment: statistics \& numerical data, Sequence Homology, Statistical}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9408942}, author = {Wei-Ping Hu and Andrzej Koli{\'n}ski and Jeffrey Skolnick} }