@article {Horwacik2011, title = {Analysis and optimization of interactions between peptides mimicking the GD2 ganglioside and the monoclonal antibody 14G2a}, journal = {International Journal of Molecular Medicine}, volume = {28}, number = {1}, year = {2011}, month = {jul}, pages = {47{\textendash}57}, abstract = {

Overexpression of the GD2 ganglioside (GD2) is a hallmark of neuroblastoma. The antigen is used in neuroblastoma diagnosis and to target newly developed therapies to cancer cells. Peptide mimetics are novel approaches in the design of antigens for vaccine development. We previously reported the isolation of five GD2-mimicking peptides from the LX-8 phage display library with the monoclonal antibody (mAb) 14G2a. The goal of our current study was to analyze and optimize the binding of the peptide mimetics to the mAb 14G2a. Therefore, we performed further experiments and supported them with molecular modeling to investigate structure-activity relationships that are the basis for the observed mimicry of GD2 by our peptides. Here, we show that the peptides have overlapping binding sites on the mAb, 14G2a and restricted specificity, as they did not crossreact with other ganglioside-specific antibodies tested. In addition we demonstrate that the phage environment was involved in the process of selection of our peptides. The AAEGD sequence taken from the viral major coat protein, p8, and added to the C-termini of the peptides \#65, \#85 and \#94 significantly improved their binding to the mAb, 14G2a. By application of analogs with amino acid substitutions and sequence truncations, we elucidated the structure-activity relationships necessary for the interactions between the 14G2a mAb and the peptide \#94 (RCNPNMEPPRCF). We identified amino acids indispensable for the observed GD2-mimicry by \#94 and confirmed a pivotal role of the disulphide bridge between the cysteine residues of \#94 for binding to the mAb 14G2a. More importantly, we report five new peptides demonstrating a significant improvement of mAb\ 14G2a binding. The experimental data were supported and expanded with molecular modeling tools. Taken together, the experimental results and the in\ silico data allowed us to probe in detail the mechanism of the molecular mimicry of GD2 by the peptides. Additionally, we significantly optimized binding of the leading peptide sequence \#94 to the mAb 14G2a. We can conclude that our findings add to the knowledge on factors governing selections of peptide mimetics from phage-display libraries.

}, keywords = {Amino Acid Sequence, Antibodies, Binding Sites, Cell Line, Gangliosides, Gangliosides: immunology, Humans, Models, Molecular, Molecular Mimicry, Molecular Sequence Data, Monoclonal, Monoclonal: chemistry, Monoclonal: immunology, Neuroblastoma, Neuroblastoma: genetics, Neuroblastoma: immunology, Peptide Library, Peptides, Peptides: chemistry, Peptides: immunology, Structure-Activity Relationship, Tumor}, issn = {1791-244X}, doi = {10.3892/ijmm.2011.655}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21455557}, author = {Irena Horwacik and Mateusz Kurcinski and Malgorzata Bzowska and Aleksandra K. Kowalczyk and Dominik Czaplicki and Andrzej Koli{\'n}ski and Hanna Rokita} } @article {Kurcinski2010, title = {Theoretical study of molecular mechanism of binding TRAP220 coactivator to Retinoid X Receptor alpha, activated by 9-cis retinoic acid}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {121}, number = {1-2}, year = {2010}, month = {jul}, pages = {124{\textendash}9}, publisher = {Elsevier Ltd}, abstract = {

Study on molecular mechanism of conformational reorientation of RXR-alpha ligand binding domain is presented. We employed CABS{\textendash}a reduced model of protein dynamics to model folding pathways of binding 9-cis retinoic acid to apo-RXR molecule and TRAP220 peptide fragment to the holo form. Based on obtained results we also propose a sequential model of RXR activation by 9-cis retinoic acid and TRAP220 coactivator. Methodology presented here may be used for investigation of binding pathways of other NR/hormone/cofactor sets.

}, keywords = {Binding Sites, Cell Nucleus, Cell Nucleus: metabolism, Computer Simulation, Crystallography, Humans, Ligands, Mediator Complex Subunit 1, Mediator Complex Subunit 1: metabolism, Models, Molecular, Molecular Conformation, Peptides, Peptides: chemistry, Protein Binding, Protein Structure, Retinoid X Receptor alpha, Retinoid X Receptor alpha: metabolism, Tertiary, Theoretical, Tretinoin, Tretinoin: metabolism, X-Ray, X-Ray: methods}, issn = {1879-1220}, doi = {10.1016/j.jsbmb.2010.03.086}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2906686\&tool=pmcentrez\&rendertype=abstract}, author = {Mateusz Kurcinski and Andrzej Koli{\'n}ski} } @article {Kurcinski2007a, title = {Hierarchical modeling of protein interactions}, journal = {Journal of Molecular Modeling}, volume = {13}, number = {6-7}, year = {2007}, month = {jul}, pages = {691{\textendash}698}, abstract = {A novel approach to hierarchical peptide-protein and protein-protein docking is described and evaluated. Modeling procedure starts from a reduced space representation of proteins and peptides. Polypeptide chains are represented by strings of alpha-carbon beads restricted to a fine-mesh cubic lattice. Side chains are represented by up to two centers of interactions, corresponding to beta-carbons and the centers of mass of the remaining portions of the side groups, respectively. Additional pseudoatoms are located in the centers of the virtual bonds connecting consecutive alpha carbons. These pseudoatoms support a model of main-chain hydrogen bonds. Docking starts from a collection of random configurations of modeled molecules. Interacting molecules are flexible; however, higher accuracy models are obtained when the conformational freedom of one (the larger one) of the assembling molecules is limited by a set of weak distance restraints extracted from the experimental (or theoretically predicted) structures. Sampling is done by means of Replica Exchange Monte Carlo method. Afterwards, the set of obtained structures is subject to a hierarchical clustering. Then, the centroids of the resulting clusters are used as scaffolds for the reconstruction of the atomic details. Finally, the all-atom models are energy minimized and scored using classical tools of molecular mechanics. The method is tested on a set of macromolecular assemblies consisting of proteins and peptides. It is demonstrated that the proposed approach to the flexible docking could be successfully applied to prediction of protein-peptide and protein-protein interactions. The obtained models are almost always qualitatively correct, although usually of relatively low (or moderate) resolution. In spite of this limitation, the proposed method opens new possibilities of computational studies of macromolecular recognition and mechanisms of assembly of macromolecular complexes.}, keywords = {Algorithms, Amino Acid Sequence, Amino Acids, Amino Acids: analysis, Carbon, Carbon: chemistry, Computer Simulation, Crystallography, Hydrogen Bonding, Models, Molecular, Monte Carlo Method, Peptides, Peptides: chemistry, Peptides: metabolism, Protein Binding, Protein Conformation, Protein Structure, Proteins, Proteins: chemistry, Proteins: metabolism, Secondary, Stereoisomerism, Theoretical, X-Ray}, issn = {0948-5023}, doi = {10.1007/s00894-007-0177-8}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17297609}, author = {Mateusz Kurcinski and Andrzej Koli{\'n}ski} } @article {Kurcinski2007, title = {Steps towards flexible docking: modeling of three-dimensional structures of the nuclear receptors bound with peptide ligands mimicking co-activators{\textquoteright} sequences}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {103}, number = {3-5}, year = {2007}, month = {mar}, pages = {357{\textendash}60}, abstract = {We developed a fully flexible docking method that uses a reduced lattice representation of protein molecules, adapted for modeling peptide-protein complexes. The CABS model (Carbon Alpha, Carbon Beta, Side Group) employed here, incorporates three pseudo-atoms per residue-Calpha, Cbeta and the center of the side group instead of full-atomic protein representation. Force field used by CABS was derived from statistical analysis of non-redundant database of protein structures. Application of our method included modeling of the complexes between various nuclear receptors (NRs) and peptide co-activators, for which three-dimensional structures are known. We tried to rebuild the native state of the complexes, starting from separated components. Accuracy of the best obtained models, calculated as coordinate root-mean-square deviation (cRMSD) between the target and the modeled structures, was under 1A, which is competitive with experimental methods, such as crystallography or NMR. Forthcoming modeling study should lead to better understanding of mechanisms of macromolecular assembly and will explain co-activators{\textquoteright} effects on receptors activity, especially on vitamin D receptor and other nuclear receptors.}, keywords = {Amino Acid Sequence, Crystallography, Cytoplasmic and Nuclear, Cytoplasmic and Nuclear: chemistry, Cytoplasmic and Nuclear: metabolism, Ligands, Models, Molecular, Molecular Mimicry, Peptides, Peptides: chemistry, Peptides: metabolism, Protein Binding, Protein Structure, Quaternary, Receptors, X-Ray}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2006.12.059}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17241780}, author = {Mateusz Kurcinski and Andrzej Koli{\'n}ski} } @article {Pokarowski2003, title = {A minimal physically realistic protein-like lattice model: designing an energy landscape that ensures all-or-none folding to a unique native state}, journal = {Biophysical Journal}, volume = {84}, number = {3}, year = {2003}, month = {mar}, pages = {1518{\textendash}26}, abstract = {A simple protein model restricted to the face-centered cubic lattice has been studied. The model interaction scheme includes attractive interactions between hydrophobic (H) residues, repulsive interactions between hydrophobic and polar (P) residues, and orientation-dependent P-P interactions. Additionally, there is a potential that favors extended beta-type conformations. A sequence has been designed that adopts a native structure, consisting of an antiparallel, six-member Greek-key beta-barrel with protein-like structural degeneracy. It has been shown that the proposed model is a minimal one, i.e., all the above listed types of interactions are necessary for cooperative (all-or-none) type folding to the native state. Simulations were performed via the Replica Exchange Monte Carlo method and the numerical data analyzed via a multihistogram method.}, keywords = {Amino Acid Motifs, Computer Simulation, Crystallography, Crystallography: methods, Energy Transfer, Entropy, Mechanical, Models, Molecular, Monte Carlo Method, Peptides, Peptides: chemistry, Protein Conformation, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Static Electricity, Stress, Tertiary}, issn = {0006-3495}, doi = {10.1016/S0006-3495(03)74964-9}, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1302725\&tool=pmcentrez\&rendertype=abstract}, author = {Piotr Pokarowski and Andrzej Koli{\'n}ski and Jeffrey Skolnick} }