@article {388, title = {Identifying knots in proteins.}, journal = {Biochemical Society Transactions}, volume = {41}, year = {2013}, month = {2013 Apr}, pages = {533-7}, abstract = {Polypeptide chains form open knots in many proteins. How these knotted proteins fold and finding the evolutionary advantage provided by these knots are among some of the key questions currently being studied in the protein folding field. The detection and identification of protein knots are substantial challenges. Different methods and many variations of them have been employed, but they can give different results for the same protein. In the present article, we review the various knot identification algorithms and compare their relative strengths when applied to the study of knots in proteins. We show that the statistical approach based on the uniform closure method is advantageous in comparison with other methods used to characterize protein knots.}, keywords = {Animals, Humans, Models, Molecular, Protein Conformation, Proteins}, issn = {1470-8752}, doi = {10.1042/BST20120339}, author = {Millett, Kenneth C and Rawdon, Eric J and Stasiak, Andrzej and Joanna I. Sulkowska} } @article {389, title = {Knot localization in proteins.}, journal = {Biochemical Society Transactions}, volume = {41}, year = {2013}, month = {2013 Apr}, pages = {538-41}, abstract = {The backbones of proteins form linear chains. In the case of some proteins, these chains can be characterized as forming linear open knots. The knot type\ of the full chain reveals only limited information about the entanglement of the chain since, for example, subchains of an unknotted protein can form knots and subchains of a knotted protein can form different types\ of knots than the entire protein. To understand fully the entanglement within the backbone of a given protein, a complete analysis of the knotting within all of the subchains of that protein is necessary. In the present article, we review efforts to characterize the full knotting complexity within individual proteins and present a matrix that conveys information about various aspects of protein knotting. For a given protein, this matrix identifies the precise localization of knotted regions and shows the knot types\ formed by all subchains. The pattern in the matrix can be considered as a knotting fingerprint of that protein. We observe that knotting fingerprints of distantly related knotted proteins are strongly conserved during evolution and discuss how some characteristic motifs in the knotting fingerprints are related to the structure of the knotted regions and their possible biological role.}, keywords = {Animals, Humans, Models, Molecular, Protein Conformation, Proteins}, issn = {1470-8752}, doi = {10.1042/BST20120329}, author = {Rawdon, Eric J and Millett, Kenneth C and Joanna I. Sulkowska and Stasiak, Andrzej} } @article {404, title = {Energy landscape of knotted protein folding.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, year = {2012}, month = {2012 Oct 30}, pages = {17783-8}, abstract = {Recent experiments have conclusively shown that proteins are able to fold from an unknotted, denatured polypeptide to the knotted, native state without the aid of chaperones. These experiments are consistent with a growing body of theoretical work showing that a funneled, minimally frustrated energy landscape is sufficient to fold small proteins with complex topologies. Here, we present a theoretical investigation of the folding of a knotted protein, 2ouf, engineered in the laboratory by a domain fusion that mimics an evolutionary pathway for knotted proteins. Unlike a previously studied knotted protein of similar length, we see reversible folding/knotting and a surprising lack of deep topological traps with a coarse-grained structure-based model. Our main interest is to investigate how evolution might further select the geometry and stiffness of the threading region of the newly fused protein. We compare the folding of the wild-type protein to several mutants. Similarly to the wild-type protein, all mutants show robust and reversible folding, and knotting coincides with the transition state ensemble. As observed experimentally, our simulations show that the knotted protein folds about ten times slower than an unknotted construct with an identical contact map. Simulated folding kinetics reflect the experimentally observed rollover in the folding limbs of chevron plots. Successful folding of the knotted protein is restricted to a narrow range of temperature as compared to the unknotted protein and fits of the kinetic folding data below folding temperature suggest slow, nondiffusive dynamics for the knotted protein.}, keywords = {Evolution, Molecular, Kinetics, Models, Molecular, Molecular Dynamics Simulation, Mutation, Protein Folding, Proteins}, issn = {1091-6490}, doi = {10.1073/pnas.1201804109}, author = {Joanna I. Sulkowska and Noel, Jeffrey K and Onuchic, Jos{\'e} N} } @article {403, title = {The unique cysteine knot regulates the pleotropic hormone leptin.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e45654}, abstract = {Leptin plays a key role in regulating energy intake/expenditure, metabolism and hypertension. It folds into a four-helix bundle that binds to the extracellular receptor to initiate signaling. Our work on leptin revealed a hidden complexity in the formation of a previously un-described, cysteine-knotted topology in leptin. We hypothesized that this unique topology could offer new mechanisms in regulating the protein activity. A combination of in silico simulation and in vitro experiments was used to probe the role of the knotted topology introduced by the disulphide-bridge on leptin folding and function. Our results surprisingly show that the free energy landscape is conserved between knotted and unknotted protein, however the additional complexity added by the knot formation is structurally important. Native state analyses led to the discovery that the disulphide-bond plays an important role in receptor binding and thus mediate biological activity by local motions on distal receptor-binding sites, far removed from the disulphide-bridge. Thus, the disulphide-bridge appears to function as a point of tension that allows dissipation of stress at a distance in leptin.}, keywords = {Cysteine, Humans, Kinetics, Leptin, MCF-7 Cells, Models, Molecular, Oxidation-Reduction, Signal Transduction}, issn = {1932-6203}, doi = {10.1371/journal.pone.0045654}, author = {Haglund, Ellinor and Joanna I. Sulkowska and He, Zhao and Feng, Gen-Sheng and Jennings, Patricia A and Onuchic, Jos{\'e} N} } @article {292, title = {13,13-Dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D$_{3}$ (2MD): total synthesis, docking to the VDR, and biological evaluation}, journal = {Bioorganic \& Medicinal Chemistry}, volume = {19}, year = {2011}, month = {2011 Dec 1}, pages = {7205-20}, abstract = {As a continuation of our studies focused on the vitamin D compounds lacking the C,D-hydrindane system, 13,13-dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D(3) (2, 2MD) were prepared by total synthesis. The known cyclohexanone 30, a precursor of the desired A-ring phosphine oxide 11, was synthesized starting with the keto acetal 13, whereas the aldehyde 12, constituting an acyclic {\textquoteright}upper{\textquoteright} building block, was obtained from the isomeric esters 34, prepared previously in our laboratory. The commercial 1,4-cyclohexanedione monoethylene ketal (13) was enantioselectively α-hydroxylated utilizing the α-aminoxylation process catalyzed by l-proline, and the introduced hydroxy group was protected as a TBS, TPDPS, and SEM ether. Then the keto group in the obtained compounds 15-17 was methylenated and the allylic hydroxylation was performed with selenium dioxide and pyridine N-oxide. After separation of the isomers, the newly introduced hydroxy group was protected and the ketal group hydrolyzed to yield the corresponding protected (3R,5R)-3,5-dihydroxycyclohexanones 30-32. The esters 34, starting compounds for the C,D-fragment 12, were first α-methylated, then reduced and the resulted primary alcohols 36 were deoxygenated using the Barton-McCombie protocol. Primary hydroxy group in the obtained diether 38 was deprotected and oxidized to furnish the aldehyde 12. The Wittig-Horner coupling of the latter with the anion of the phosphine oxide 11, followed by hydroxyl deprotection furnished two isomeric 13,13-dimethyl-des-C,D analogues of 2MD (compounds 10 and 42) differing in configuration of their 7,8-double bond. Pure vitamin D analogues were isolated by HPLC and their biological activity was examined. The in vitro tests indicated that, compared to the analogue 7, unsubstituted at C-13, the synthesized vitamin D analogue 10 showed markedly improved VDR binding ability, significantly enhanced HL-60 differentiation activity as well as increased transcriptional potency. Docking simulations provided a rational explanation for the observed binding affinity of these ligands to the VDR. Biological in vivo tests proved that des-C,D compound 10 retained some intestinal activity. Its geometrical isomer 42 was devoid of any biological activity.}, keywords = {Animals, Calcitriol, Cell Differentiation, Crystallography, X-Ray, HL-60 Cells, Humans, Male, Models, Molecular, Molecular Conformation, Rats, Receptors, Calcitriol, Structure-Activity Relationship}, issn = {1464-3391}, doi = {10.1016/j.bmc.2011.09.048}, author = {Katarzyna Plonska-Ocypa and Izabela Sibilska and Rafal R. Sicinski and Wanda Sicinska and Lori A. Plum and Hector F. DeLuca} } @article {409, title = {Slipknotting upon native-like loop formation in a trefoil knot protein.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107}, year = {2010}, month = {2010 Aug 31}, pages = {15403-8}, abstract = {Protein knots and slipknots, mostly regarded as intriguing oddities, are gradually being recognized as significant structural motifs. Recent experimental results show that knotting, starting from a fully extended polypeptide, has not yet been observed. Understanding the nucleation process of folding knots is thus a natural challenge for both experimental and theoretical investigation. In this study, we employ energy landscape theory and molecular dynamics to elucidate the entire folding mechanism. The full free energy landscape of a knotted protein is mapped using an all-atom structure-based protein model. Results show that, due to the topological constraint, the protein folds through a three-state mechanism that contains (i) a precise nucleation site that creates a correctly twisted native loop (first barrier) and (ii) a rate-limiting free energy barrier that is traversed by two parallel knot-forming routes. The main route corresponds to a slipknot conformation, a collapsed configuration where the C-terminal helix adopts a hairpin-like configuration while threading, and the minor route to an entropically limited plug motion, where the extended terminus is threaded as through a needle. Knot formation is a late transition state process and results show that random (nonspecific) knots are a very rare and unstable set of configurations both at and below folding temperature. Our study shows that a native-biased landscape is sufficient to fold complex topologies and presents a folding mechanism generalizable to all known knotted protein topologies: knotting via threading a native-like loop in a preordered intermediate.}, keywords = {Algorithms, Archaea, Archaeal Proteins, Crystallization, Databases, Protein, Models, Molecular, Molecular Dynamics Simulation, Protein Conformation, Protein Folding, Protein Multimerization, Protein Structure, Secondary, Protein Structure, Tertiary, Thermodynamics}, issn = {1091-6490}, doi = {10.1073/pnas.1009522107}, author = {Noel, Jeffrey K and Joanna I. Sulkowska and Onuchic, Jos{\'e} N} } @article {414, title = {Dodging the crisis of folding proteins with knots.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {106}, year = {2009}, month = {2009 Mar 3}, pages = {3119-24}, abstract = {Proteins with nontrivial topology, containing knots and slipknots, have the ability to fold to their native states without any additional external forces invoked. A mechanism is suggested for folding of these proteins, such as YibK and YbeA, that involves an intermediate configuration with a slipknot. It elucidates the role of topological barriers and backtracking during the folding event. It also illustrates that native contacts are sufficient to guarantee folding in approximately 1-2\% of the simulations, and how slipknot intermediates are needed to reduce the topological bottlenecks. As expected, simulations of proteins with similar structure but with knot removed fold much more efficiently, clearly demonstrating the origin of these topological barriers. Although these studies are based on a simple coarse-grained model, they are already able to extract some of the underlying principles governing folding in such complex topologies.}, keywords = {Kinetics, Models, Molecular, Protein Folding, Protein Structure, Tertiary, Proteins}, issn = {1091-6490}, doi = {10.1073/pnas.0811147106}, author = {Joanna I. Sulkowska and Su{\l}kowski, Piotr and Onuchic, Jos{\'e}} } @article {412, title = {Mechanical strength of 17,134 model proteins and cysteine slipknots.}, journal = {PLoS Comput Biol}, volume = {5}, year = {2009}, month = {2009 Oct}, pages = {e1000547}, abstract = {A new theoretical survey of proteins{\textquoteright} resistance to constant speed stretching is performed for a set of 17,134 proteins as described by a structure-based model. The proteins selected have no gaps in their structure determination and consist of no more than 250 amino acids. Our previous studies have dealt with 7510 proteins of no more than 150 amino acids. The proteins are ranked according to the strength of the resistance. Most of the predicted top-strength proteins have not yet been studied experimentally. Architectures and folds which are likely to yield large forces are identified. New types of potent force clamps are discovered. They involve disulphide bridges and, in particular, cysteine slipknots. An effective energy parameter of the model is estimated by comparing the theoretical data on characteristic forces to the corresponding experimental values combined with an extrapolation of the theoretical data to the experimental pulling speeds. These studies provide guidance for future experiments on single molecule manipulation and should lead to selection of proteins for applications. A new class of proteins, involving cysteine slipknots, is identified as one that is expected to lead to the strongest force clamps known. This class is characterized through molecular dynamics simulations.}, keywords = {Amino Acids, Cysteine, elasticity, Humans, Models, Molecular, Molecular Dynamics Simulation, Protein Folding, Proteins, Tensile Strength}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000547}, author = {Sikora, Mateusz and Joanna I. Sulkowska and Cieplak, Marek} } @article {416, title = {Selection of optimal variants of Go-like models of proteins through studies of stretching.}, journal = {Biophys J}, volume = {95}, year = {2008}, month = {2008 Oct}, pages = {3174-91}, abstract = {The Go-like models of proteins are constructed based on the knowledge of the native conformation. However, there are many possible choices of a Hamiltonian for which the ground state coincides with the native state. Here, we propose to use experimental data on protein stretching to determine what choices are most adequate physically. This criterion is motivated by the fact that stretching processes usually start with the native structure, in the vicinity of which the Go-like models should work the best. Our selection procedure is applied to 62 different versions of the Go model and is based on 28 proteins. We consider different potentials, contact maps, local stiffness energies, and energy scales--uniform and nonuniform. In the latter case, the strength of the nonuniformity was governed either by specificity or by properties related to positioning of the side groups. Among them is the simplest variant: uniform couplings with no i, i + 2 contacts. This choice also leads to good folding properties in most cases. We elucidate relationship between the local stiffness described by a potential which involves local chirality and the one which involves dihedral and bond angles. The latter stiffness improves folding but there is little difference between them when it comes to stretching.}, keywords = {Analysis of Variance, Biomechanical Phenomena, Models, Molecular, Protein Conformation, Protein Folding, Proteins, Reproducibility of Results, Temperature, Thermodynamics}, issn = {1542-0086}, doi = {10.1529/biophysj.107.127233}, author = {Joanna I. Sulkowska and Cieplak, Marek} } @article {419, title = {Stretching to understand proteins - a survey of the protein data bank.}, journal = {Biophys J}, volume = {94}, year = {2008}, month = {2008 Jan 1}, pages = {6-13}, abstract = {We make a survey of resistance of 7510 proteins to mechanical stretching at constant speed as studied within a coarse-grained molecular dynamics model. We correlate the maximum force of resistance with the native structure, predict proteins which should be especially strong, and identify the nature of their force clamps.}, keywords = {Computer Simulation, Databases, Protein, elasticity, Models, Chemical, Models, Molecular, Proteins, Sequence Analysis, Protein, Stress, Mechanical, Structure-Activity Relationship}, issn = {1542-0086}, doi = {10.1529/biophysj.107.105973}, author = {Joanna I. Sulkowska and Cieplak, Marek} } @article {417, title = {Tightening of knots in proteins.}, journal = {Phys Rev Lett}, volume = {100}, year = {2008}, month = {2008 Feb 8}, pages = {058106}, abstract = {We perform theoretical studies of stretching of 20 proteins with knots within a coarse-grained model. The knot{\textquoteright}s ends are found to jump to well defined sequential locations that are associated with sharp turns, whereas in homopolymers they diffuse around and eventually slide off. The waiting times of the jumps are increasingly stochastic as the temperature is raised. Knots typically do not return to their native locations when a protein is released after stretching.}, keywords = {Algorithms, Diffusion, Models, Molecular, Protein Conformation, Solvents, Stochastic Processes, Temperature}, issn = {0031-9007}, author = {Joanna I. Sulkowska and Su{\l}kowski, Piotr and Szymczak, P and Cieplak, Marek} } @article {295, title = {Computational analysis of the active sites in binary and ternary complexes of the vitamin D receptor}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {103}, year = {2007}, month = {2007 Mar}, pages = {305-9}, abstract = {We have developed a program CCOMP that compares overlapping fragments of two protein complexes and identifies differently oriented amino acids. CCOMP initially performs a sequence alignment of the analyzed receptors, then superimposes the corresponding aligned residues, and finally calculates the root mean square deviation (RMSD) of individual atoms, every amino acid and the entire complex. Thus, amino acids important for functional differences between both complexes can be detected. Application of CCOMP to 1alpha,25-(OH)(2)D(3)-hVDR (1DB1) [Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 5491] and 1alpha,25-(OH)(2)D(3)-rVDR-peptide (1RK3) [Biochemistry 43 (2004) 4101] complexes revealed that the peptide (KNHPMLMNLLKDN) mimicking a co-activator sequence significantly changes the side chain conformation of 35 amino acids. Four of these residues (K242, I256, K260, E416) actually contact the peptide, but all of them are essential for biological activity. Only two (L309 and L400) of the 35 differently oriented amino acids contact the ligand. Interestingly, when the peptide is present (1RK3) leucine 400 shifts closer (0.7A) to the vitamin D 26-methyl group. Applying the CCOMP and DSSP programs to binary and ternary VDR complexes also resulted in establishing that seven amino acids (I238, S252, I256, L413, L415, E416, V417) exhibit significant differences in solvent accessibility and are capable of interacting with co-activators.}, keywords = {Binding Sites, Biomimetic Materials, Computer Simulation, Models, Molecular, Peptides, Protein Binding, Protein Structure, Tertiary, Receptors, Calcitriol, Solvents}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2006.12.077}, author = {Wanda Sicinska and Piotr Rotkiewicz} } @article {254, title = {Clustering as a supporting tool for structural drug design}, journal = {Acta Poloniae Pharmaceutica. Drug Research}, volume = {63}, year = {2006}, month = {2006 Sep-Oct}, pages = {436-8}, keywords = {Cluster Analysis, Computer Simulation, Drug Design, Ligands, Models, Molecular, Molecular Structure, Protein Binding}, issn = {0001-6837}, author = {Dominik Gront and Mateusz Kurcinski and Andrzej Koli{\'n}ski} } @article {421, title = {Thermal unfolding of proteins.}, journal = {J Chem Phys}, volume = {123}, year = {2005}, month = {2005 Nov 15}, pages = {194908}, abstract = {Thermal unfolding of proteins is compared to folding and mechanical stretching in a simple topology-based dynamical model. We define the unfolding time and demonstrate its low-temperature divergence. Below a characteristic temperature, contacts break at separate time scales and unfolding proceeds approximately in a way reverse to folding. Features in these scenarios agree with experiments and atomic simulations on titin.}, keywords = {Chemistry, Physical, Computer Simulation, Connectin, Kinetics, Models, Molecular, Molecular Conformation, Muscle Proteins, Protein Conformation, Protein Denaturation, Protein Folding, Protein Kinases, Protein Structure, Secondary, Proteins, Temperature, Time Factors}, issn = {0021-9606}, doi = {10.1063/1.2121668}, author = {Cieplak, Marek and Joanna I. Sulkowska} } @article {299, title = {2-Methylene analogs of 1alpha-hydroxy-19-norvitamin D3: synthesis, biological activities and docking to the ligand binding domain of the rat vitamin D receptor}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {89-90}, year = {2004}, month = {2004 May}, pages = {13-7}, abstract = {In continuing efforts towards the synthesis of biologically active vitamin D compounds of potential therapeutic value, new 2-methylene-1alpha-hydroxy-19-norvitamin D(3) analogs 3 and 4 with modified alkyl side chains have been synthesized. The key synthetic step involved Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann type ketones 9, possessing different 17beta-alkyl substituents, with the phosphine oxide 10 prepared from (-)-quinic acid. The prepared vitamins 3 and 4 were ca. eight times less potent than 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) (1) in binding to the rat intestinal vitamin D receptor (VDR). In comparison with the hormone 1 they exhibited slightly lower cellular HL-60 differentiation activity. When tested in vivo; the analog 3 was characterized by very high bone calcium mobilizing potency and intestinal calcium transport activity. Unexpectedly, the 25-methyl compound 4 showed marked calcemic activity in both assays. Computational docking of the vitamin 3 into the binding pocket of the rat vitamin D receptor is also reported.}, keywords = {Animals, Binding Sites, Calcitriol, Female, HL-60 Cells, Humans, Hydrocarbons, Ligands, Methane, Mice, Models, Molecular, Rats, Receptors, Calcitriol}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2004.03.103}, author = {Pawel Grzywacz and Lori A. Plum and Wanda Sicinska and Rafal R. Sicinski and Jean M. Prahl and Hector F. DeLuca} } @article {298, title = {Model of three-dimensional structure of VDR bound with Vitamin D3 analogs substituted at carbon-2}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {89-90}, year = {2004}, month = {2004 May}, pages = {107-10}, abstract = {All Vitamin D analogs possessing the A ring modified at C-2 and showing calcemic activities nest themselves in the VDR binding pocket, oriented towards Tyr 143. Such topology resembles the position of the Vitamin D hormone in hVDRmt [Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 5491]. Conversely, inactive 2beta-methyl-19-nor-analogs anchor the receptor cavity in a distinguishably different manner, namely by their side chain. Moreover, these inactive vitamins have a different conformation around C(6)-C(7) bond. Topology of modeled complexes suggests that a Vitamin D analog will be biologically active if its intercyclic 5,7-diene moiety assumes parallel position to tryptophan aromatic rings; such orientation allows for creating pi-pi interactions. The broad comparison of calcemic activities of the analogs, and their interactions with VDR, revealed that specific hydrophobic contacts are involved in bone calcium mobilization (BCM). These contacts occur between 21-methyl group and a few amino acids (V296, L305 and L309), conserved in the nuclear receptor superfamily. In the inactive 2beta-methyl-19-nor analogs such contacts do not exist. We speculate that two hydrophobic receptor patches, being in close contact with ligand methyl groups, might influence interaction with co-modulators involved in calcium homeostasis.}, keywords = {Animals, Calcium, Carbon, Cholecalciferol, Ligands, Models, Molecular, Molecular Conformation, Rats, Receptors, Calcitriol}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2004.03.102}, author = {Wanda Sicinska and Piotr Rotkiewicz and Hector F. DeLuca} } @article {300, title = {Solvent polarity and hydrogen-bonding effects on the nitrogen NMR shieldings of N-nitrosamines and DFT calculations of the shieldings of C-, N-, and O-nitroso systems}, journal = {Journal of Magnetic Resonance}, volume = {164}, year = {2003}, month = {2003 Oct}, pages = {212-9}, abstract = {High-precision nitrogen NMR shieldings, bulk susceptibility corrected, are reported for dimethyl-N-nitrosamine (I) and diethyl-N-nitrosamine (II) in a variety of solvents which represent a wide range of solvent properties from the point of view of polarity as well as hydrogen bond donor and acceptor strength. The observed range of solvent-induced nitrogen shielding variations of (I) and (II) is significant for the amino-type nitrogens, up to about 16 ppm, and originates essentially from the deshielding effect of the increasing polarity of solvent. On the other side, the nitroso nitrogen shieldings reveal an even stronger response to solvent effects, within about 20 ppm, but in this case the increasing polarity and hydrogen bond donor strength of solvent produce enhanced shielding. DFT quantum-mechanical calculations using the GIAO/B3PW91/6-311++G** approach and geometry optimizations employing the same basis set and hybrid density functionals show an excellent correlation with the experimental data on C-, N-, and O-nitroso moieties and reproduce not only major changes but also most of the subtle variations in the experimental nitrogen shieldings of the nitroso systems as a whole. A combination of the calculations involving the corresponding N and O-protonated species and the trends observed in the solvent-induced nitrogen shielding variations shows clearly that the prime acceptor site for hydrogen bonding is the nitroso oxygen atom.}, keywords = {Algorithms, Binding Sites, Carbon, Computer Simulation, Hydrogen Bonding, Macromolecular Substances, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Conformation, Molecular Structure, Nitrogen, Nitrogen Isotopes, Nitrosamines, Nitroso Compounds, Oxygen, solutions, Solvents}, issn = {1090-7807}, author = {Michal Witanowski and Zenobia Biedrzycka and Wanda Sicinska and Zbigniew Grabowski} } @article {291, title = {TOUCHSTONEX: protein structure prediction with sparse NMR data}, journal = {Proteins}, volume = {53}, year = {2003}, month = {2003 Nov 1}, pages = {290-306}, abstract = {TOUCHSTONEX, a new method for folding proteins that uses a small number of long-range contact restraints derived from NMR experimental NOE (nuclear Overhauser enhancement) data, is described. The method employs a new lattice-based, reduced model of proteins that explicitly represents C(alpha), C(beta), and the sidechain centers of mass. The force field consists of knowledge-based terms to produce protein-like behavior, including various short-range interactions, hydrogen bonding, and one-body, pairwise, and multibody long-range interactions. Contact restraints were incorporated into the force field as an NOE-specific pairwise potential. We evaluated the algorithm using a set of 125 proteins of various secondary structure types and lengths up to 174 residues. Using N/8 simulated, long-range sidechain contact restraints, where N is the number of residues, 108 proteins were folded to a C(alpha)-root-mean-square deviation (RMSD) from native below 6.5 A. The average RMSD of the lowest RMSD structures for all 125 proteins (folded and unfolded) was 4.4 A. The algorithm was also applied to limited experimental NOE data generated for three proteins. Using very few experimental sidechain contact restraints, and a small number of sidechain-main chain and main chain-main chain contact restraints, we folded all three proteins to low-to-medium resolution structures. The algorithm can be applied to the NMR structure determination process or other experimental methods that can provide tertiary restraint information, especially in the early stage of structure determination, when only limited data are available.}, keywords = {Algorithms, Amino Acids, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Proteins, Staphylococcal Protein A}, issn = {1097-0134}, doi = {10.1002/prot.10499}, author = {Wei Li and Yang Zhang and Daisuke Kihara and Yuanpeng Janet Huang and Deyou Zheng and Gaetano T. Montelione and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {290, title = {2-Ethyl and 2-ethylidene analogues of 1alpha,25-dihydroxy-19-norvitamin D(3): synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain.}, journal = {Journal of Medicinal Chemistry}, volume = {45}, year = {2002}, month = {2002 Aug 1}, pages = {3366-80}, abstract = {Novel 19-nor analogues of 1alpha,25-dihydroxyvitamin D(3) were prepared and substituted at C-2 with an ethylidene group. The synthetic pathway was via Wittig-Horner coupling of the corresponding A-ring phosphine oxides with the protected 25-hydroxy Grundmann{\textquoteright}s ketones. Selective catalytic hydrogenation of 2-ethylidene analogues provided the 2alpha- and 2beta-ethyl compounds. The 2-ethylidene-19-nor compounds with a methyl group from the ethylidene moiety in a trans relationship to the C(6)-C(7) bond (E-isomers) were more potent than the corresponding Z-isomers and the natural hormone in binding to the vitamin D receptor. Both geometrical isomers (E and Z) of (20S)-2-ethylidene-19-norvitamin D(3) and both 2alpha-ethyl-19-norvitamins (in the 20R- and 20S-series) have much higher HL-60 differentiation activity than does 1alpha,25-(OH)(2)D(3). Both E-isomers (20R and 20S) of 2-ethylidene vitamins are characterized by very high calcemic activity in rats. The three-dimensional structure model of the rat vitamin D receptor and the computational docking of four synthesized (20R)-19-norvitamin D(3) analogues into its binding pocket are also reported.}, keywords = {Animals, Binding Sites, Biological Transport, Calcitriol, Calcium, Cell Differentiation, Chromatography, High Pressure Liquid, HL-60 Cells, Humans, Intestinal Mucosa, Ligands, Magnetic Resonance Spectroscopy, Male, Models, Molecular, Molecular Conformation, Rats, Receptors, Calcitriol, Spectrophotometry, Ultraviolet, Structure-Activity Relationship, Swine}, issn = {0022-2623}, author = {Rafal R. Sicinski and Piotr Rotkiewicz and Andrzej Koli{\'n}ski and Wanda Sicinska and Jean M. Prahl and Connie M. Smith and Hector F. DeLuca} } @article {287, title = {Monte Carlo simulations of protein folding. I. Lattice model and interaction scheme}, journal = {Proteins}, volume = {18}, year = {1994}, month = {1994 Apr}, pages = {338-52}, abstract = {A new hierarchical method for the simulation of the protein folding process and the de novo prediction of protein three-dimensional structure is proposed. The reduced representation of the protein alpha-carbon backbone employs lattice discretizations of increasing geometrical resolution and a single ball representation of side chain rotamers. In particular, coarser and finer lattice backbone descriptions are used. The coarser (finer) lattice represents C alpha traces of native proteins with an accuracy of 1.0 (0.7) A rms. Folding is simulated by means of very fast Monte Carlo lattice dynamics. The potential of mean force, predominantly of statistical origin, contains several novel terms that facilitate the cooperative assembly of secondary structure elements and the cooperative packing of the side chains. Particular contributions to the interaction scheme are discussed in detail. In the accompanying paper (Kolinski, A., Skolnick, J. Monte Carlo simulation of protein folding. II. Application to protein A, ROP, and crambin. Proteins 18:353-366, 1994), the method is applied to three small globular proteins.}, keywords = {Amino Acid Sequence, Amino Acids, Computer Simulation, Hydrogen Bonding, Models, Chemical, Models, Molecular, Models, Theoretical, Molecular Sequence Data, Monte Carlo Method, Protein Folding, Protein Structure, Tertiary}, issn = {0887-3585}, doi = {10.1002/prot.340180405}, author = {Andrzej Koli{\'n}ski and Jeffrey Skolnick} }