@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 {Gniewek2010, title = {Coarse-grained Monte Carlo simulations of mucus: structure, dynamics, and thermodynamics}, journal = {Biophysical Journal}, volume = {99}, number = {11}, year = {2010}, month = {dec}, pages = {3507{\textendash}16}, publisher = {Biophysical Society}, abstract = {A simple coarse-grained model of mucus structure and dynamics is proposed and evaluated. The model is based on simple cubic, face-centered lattice representation. Mucins are simulated as lattice chains in which each bead of the model chains represents a mucin domain, equivalent to its Kuhn segment. The remaining lattice sites are considered to be occupied by the solvent. Model mucins consist of three types of domains: polar (glycosylated central segments), hydrophobic, and cysteine-rich, located at the terminal part of the mucin chains. The sequence of these domains mimics the sequence of real mucins. Static and dynamic properties of the system were studied by means of Monte Carlo dynamics. It was shown that the model system undergoes sol-gel transition and that the interactions between hydrophobic domains are responsible for the transition and characteristic properties of the dynamic network in the gel phase. Cysteine-rich domains are essential for frictional properties of the system. Structural and dynamic properties of the model mucus observed in simulations are in qualitative agreement with known experimental facts and provide mechanistic explanation of complex properties of real mucus.}, keywords = {Cysteine, Cysteine: chemistry, Diffusion, Gels, Humans, Hydrophobic and Hydrophilic Interactions, Molecular Dynamics Simulation, Monte Carlo Method, Mucins, Mucins: chemistry, Mucus, Mucus: chemistry, Protein Structure, Tertiary, Thermodynamics}, issn = {1542-0086}, doi = {10.1016/j.bpj.2010.09.047}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2998598\&tool=pmcentrez\&rendertype=abstract}, author = {Pawel Gniewek and Andrzej Koli{\'n}ski} } @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} }