"In silico structural biology correlated with experiment"
The Department of Bioinformatics & Structural Biochemistry (DBSB) was set in 1999 aiming to consistently implement computational biology techniques - bioinformatics, modeling, simulation - and use them to guide experimental research in molecular biology and biochemistry.
Historically the main focus of DBSB was the investigation of glycoprotein (GP) folding & degradation and the relation between glycosylation and GP structure. On this line DBSB works in co-ordination with the Department of Molecular Cell Biology and colleagues from the Department of Biochemistry, University of Oxford, UK. Results have shed light onto the structure of glycans attached to the nascent protein chain and their role in the ER quality control and degradation [1,7-5,14,20,33]. The way glycosylation affects GP structure was also assessed using bioinformatics approach. To this end DBSB has developed SAGS: "Structural Assessment of Glycosylation Sites" - a comprehensive Data Base curating structural information on glycans and glycoproteins, with significant applications in modeling biological systems at molecular level [4,13,15,20-21,32].
DBSB was also involved in more general aspects of the physics of protein folding and structure. Configurations along the folding pathway and in the native state are degenerate and the experimental data has to be interpreted in the frame of statistical mechanics. In collaboration with colleagues from CEA Saclay and Heidelberg University we have investigated unfolded and native protein states using molecular simulation in combination with Small Angle and Quasielastic Neutron Scattering.
These studies have resulted in a better understanding of the folding process and the motility gradients in proteins explaining their stability and ability to interact with other molecules [2,3,8-12].
Combining bioinformatics with principles of protein folding and dynamics results in many applications in molecular life sciences such as building probabilistic models when the experimental structures are not available, or probing in silico biomolecular interactions.
Presently a significant part of our work is devoted to developing techniques in this field and applying them to a variety of problems in structural biology and molecular medicine. For example in collaboration with colleagues from IBAR and Oxford University we continue to investigate the structural aspects of processes along the secretory pathway; with colleagues from Yale, Levin Cancer Institute USA or Warsaw University Poland we are looking into protein-DNA interactions in a number of systems relevant in molecular medicine & biotechnology[29,34,36,38,42,43]; with groups from Universities of Wageningen, Haifa, Zurich, MPI-Koln, INRA-France etc we are involved in investigating the molecular basis of plant-pathogen interaction [16-17,22-24,26-27,31,39,41,45-47].
In 2012 Adina Milac (researcher ID: C-1070-2011) joined the DBSB coming from National Institute of Health, NIH Bethesda, USA where she carried out two PostDoc stages in Lawrence Tabak's and Robert Guy's lab. Adina brought in fresh molecular modeling & simulation techniques and new research topics related to structure-function relation in ion-channel systems and drug-design [19,27,28,34,38,44].
Along the years, DBSB work was financed by a large number of national and international grants among of which we mention 1 EU-IP-FP6 ("Bioexploit": 2005-2011); 1 EU-FP5 ("Nonema": 2001-2004); 2 UK - Wellcome Trust ( "Tyrosinase Folding": 1998-2001; "Glycoprotein Database": 2002-2005) or the national grant PN-II-ID-PCE 168 ("in silico": 2007-2011).
The models generated so far in this process allowed us to make predictions upon systems behavior. Subsequently predictions were successfully validated experimentally and resulted in a better understanding of the molecular bases underlying the investigated biological functions - some of them with potentially important applications in molecular medicine, biotechnology and pharmacology [16-52].
Research in the above mentioned fields continues and is currently financed within the frame of a number of grants and research collaborations such as CNSC PN2-ID-PCE-2011-3-0342 " Modeling molecular complexes and assemblies with experimental and bioinformatic constraints" (2011-2016).
A-JP is currently member of the MC of COST Action "Sustain" FA1208-11941: " Pathogen-informed strategies for sustainable broad-spectrum crop resistance" (2013-2018) and also Co-PI in the USA-NIH grant 4R37 AI032524 "Structure of RAG1-RAG2-DNA complexes" (2012-2017) carried by David Schatz. In this project a key role is played by Marius Surleac, who also is involved in a related European collaboration of DBSB funded by ERANET-HIVERA PNIII-P3-53/2016-2019: "INinRAGI".
We also have ongoing projects to developing new statistical and machine learning techniques useful in simulation and bioinformatics. Here the central stage was taken by Laurentiu Spiridon returned at the fall of 2016 from PostDoc stages at Illinois Institute of Thechnology where he has developped extremely efficient, robotic based algorithms for MC simulations. Laurentiu will be assisted by Teodor, our MSc Student and Eliza Martin who runs also her onw PhD on Statistical Techniques in Bioinformatics with a focus on Bayesian Statistics and Machine Learning techniques for structure prediction.
Another priority of DBSB, in which Cristian Munteanu plays the key role is now to coupling computational techniques with Mass Spectrometry, Surface Plasmon Resonance and data derived from the Highthroughput Drug Screening Platform of IBAR, aiming to step up the scale of biological system investigation to global proteome and interactome level [35,40, 44].
All the above computational work is supervised by our expert in Parallel Computing Marius Micluta who plays the central role in managing our High Perforance Computing Centre - the key element of all our Biocomputing / Bioinformatics programs and projects.
Manica G, Ghenea S, Munteanu CVA, Martin EC, Butnaru C, Surleac M, Chiritoiu GN, Alexandru PR, Petrescu AJ, Petrescu SM. "EDEM3 Domains Cooperate to Perform Its Overall Cell Functioning." Int J Mol Sci. 22(4):2172 (2021).
Manoliu LCE, Martin EC, Milac AL, Spiridon L. "Effective Use of Empirical Data for Virtual Screening against APJR GPCR Receptor." Molecules. 26(16):4894 (2021)
Mernea M, Martin EC, Petrescu AJ*, Avram S*. "Deep learning in the quest for compound nomination for fighting COVID-19." Curr Med Chem. 28(28):5699-5732. (2021)
Baudin M, Martin EC, Sass C, Hassan JA, Bendix C, Sauceda R, Diplock N, Specht CD, Petrescu AJ, Lewis JD. "A natural diversity screen in Arabidopsis thaliana reveals determinants for HopZ1a recognition in the ZAR1-ZED1 immune complex." Plant Cell Environ.;44(2):629-644 (2021)
Martin EC, Vicari C, Tsakou-Ngouafo L, Pontarotti P, Petrescu AJ, Schatz DG. "Identification of RAG-like transposons in protostomes suggests their ancient bilaterian origin." Mob DNA. 11, 17 (2020).
Spiridon L, Şulea TA, Minh DDL, Petrescu AJ. "Robosample: A rigid-body molecular simulation program based on robot mechanics." Biochim Biophys Acta Gen Subj. 1864(8), 129616. (2020)
Martin EC, Sukarta OCA, Spiridon L, Grigore LG, Constantinescu V, Tacutu R, Goverse A, Petrescu A-J, "LRRpredictor - A New LRR Motif Detection Method for Irregular Motifs of Plant NLR Proteins Using an Ensemble of Classifiers", Genes 11(3), 286-300 (2020)
Baudin M, Schreiber KJ, Martin EC, Petrescu AJ, Lewis JD. "Structure-function analysis of ZAR1 immune receptor reveals key molecular interactions for activity." Plant J. 101(2), 352-370 (2020)
Zhang Y, Cheng TC, Huang G, Lu Q, Surleac MD, Mandell JD, Pontarotti P, Petrescu AJ, Xu A, Xiong Y, Schatz DG. "Transposon molecular domestication and the evolution of the RAG recombinase.", Nature. 569:79-84 (2019).
Munteanu CVA, Chiriţoiu GN, Petrescu AJ, Petrescu SM. "Profiling Optimal Conditions for Capturing EDEM Proteins Complexes in Melanoma Using Mass Spectrometry." Adv.Exp.Med.Biol. 1140:155-167 (2019).
Sarbu M, Ica R, Petrut A, Vukelić Ž, Munteanu CVA, Petrescu AJ, Zamfir AD. "Gangliosidome of human anencephaly: A high resolution multistage mass spectrometry study.", Biochimie. 163:142-151 (2019)
Tanase CI; Cocu F; Draghici C; Hanganu A; Pintilie L; Maganu M; Munteanu CVA; Shova S Secondary compounds in the catalytic hydrogenation of enone and allylic alcohol prostaglandin intermediates: isolation, characterization, and X-ray crystallography", New J.Chem 43, 7582-7599 (2019)
Ciubotaru M, Musat MG, Surleac M, Ionita E, Petrescu AJ, Abele E, Abele R. "The Design of New HIV-IN Tethered Bifunctional Inhibitors using Multiple Microdomain Targeted Docking." Curr Med Chem. 26:2574-2600 (2019).
Wróblewski T, Spiridon L, Martin EC, Petrescu AJ, Cavanaugh K, Jose-Truco M, Xu H, Gozdowski D, Pawłowski K, Michelmore RW, Takken FLW.. "Genome-wide functional analyses of plant coiled–coil NLR-type pathogen receptors reveal essential roles of their N-terminal domain in oligomerization, networking, and immunity." PLOS Biology 16: e2005821 (2018)
Slootweg EJ, Spiridon LN, Martin EC, Tameling WIL, Townsend PD, Pomp R, Roosien J, Drawska O, Sukarta OCA, Schots A, Borst JW, Joosten MHAJ, Bakker J, Smant G, Cann MJ, Petrescu AJ, Goverse A. "Distinct Roles of Non-Overlapping Surface Regions of the Coiled-Coil Domain in the Potato Immune Receptor Rx1." Plant Physiol. 178:1310-1331 (2018)
Tanase CI; Draghici C; Shova S; Hanganu A; Gal E; Munteanu CVA "A long-range tautomeric effect on a new Schiff isoniazid analogue, evidenced by NMR study and X- ray crystallography" New J.Chem. 42, 14459-14468 (2018)
Avram S, Milac AL, Borcan LC, Mihailescu D, Borcan F, Castanho M. "Designing of Artificial Peptides for an Improved Antiviral Activity", Curr.Proteomics 15, 258-266 (2018)
Avram S, Milac AL, Mernea M, Alexandrescu IM, Borcan LC, Borcan F. "Predicted Mechanism of Antiasthmatic Drugs in Depression Based on Their Interaction with SERT and 5-HT1A Receptors", Curr.Enz.Inhib. 14, 51-60 (2018)
Norris EJ, Jones WD, Surleac MD, Petrescu AJ, Destephanis D, Zhang Q, Hamadeh I, Kneisl J, Livasy CA, Ganapathi RN, Tait DL, Ganapathi MK. "Clonal lineage of high grade serous ovarian cancer in a patient with neurofibromatosis type 1." Gynecol Oncol Rep. 23:41-44 (2018).
Kozuki T, Chikamori K, Surleac MD, Micluta MA, Petrescu AJ, Norris EJ, Elson P, Hoeltge GA, Grabowski DR, Porter ACG, Ganapathi RN, Ganapathi MK . "Roles of the C-terminal domains of topoisomerase IIa and topoisomerase IIß in regulation of the decatenation checkpoint". Nucleic Acids Res. 45:5995-6010 (2017)
Spiridon L, Minh DDL. “Hamiltonian Monte Carlo with Constrained Molecular Dynamics as Gibbs Sampling.” J Chem Theory Comput. 13:4649-4659 (2017)
Butnaru CM, Chiritoiu MB, Chiritoiu GN, Petrescu SM, Petrescu AJ. "Inhibition of N-glycan processing modulates the network of EDEM3 interactors" Biochem Biophys Res Commun. 486:978-984 (2017)
Sarbu M; Dehelean L; Munteanu CVA; Vukelic Z; Zamfir AD, "Assessment of ganglioside age-related and topographic specificity in human brain by Orbitrap mass spectrometry" Anal.Biochem. 521, 40-54 (2017)
Ruta LL, Kissen R, Nicolau I, Neagoe AD, Petrescu AJ, Bones AM, Farcasanu IC. "Heavy metal accumulation by Saccharomyces cerevisiae cells armed with metal binding hexapeptides targeted to the inner face of the plasma membrane." Appl Microbiol Biotechnol. 101:5749-5763 (2017)
Famiglietti AL, Wei Z, Beres TM, Milac AL, Tran DT, Patel D, Angerer RC, Angerer LM, Tabak LA. “Characterization and expression analysis of Galnts in developing Strongylocentrotus purpuratus embryos”. PLoS One. 12:e0176479 (2017).
Rajaraman J, Douchkov D, Hensel G, Stefanato FL, Gordon A, Ereful N, Caldararu OF, Petrescu AJ, Kumlehn J, Boyd LA, Schweizer P, "An LRR/Malectin Receptor-Like Kinase Mediates Resistance to Non-adapted and Adapted Powdery Mildew Fungi in Barley and Wheat." Front Plant Sci. 7:1836-1844 (2016).
Diaz-Granados A, Petrescu AJ, Goverse A, Smant G. "SPRYSEC Effectors: A Versatile Protein-Binding Platform to Disrupt Plant Innate Immunity." Front Plant Sci. 7:1575-1588 (2016)
De Oliveira AS, Koolhaas I, Boiteux LS, Caldararu OF, Petrescu AJ, Oliveira Resende R, Kormelink R. "Cell death triggering and effector recognition by Sw-5 SD-CNL proteins from resistant and susceptible tomato isolines to Tomato spotted wilt virus." Mol Plant Pathol. 17:1442-1454 (2016)
Popa IL, Milac AL, Sima LE, Alexandru PR, Pastrama F, Munteanu CVA, Negroiu G. "Cross-talk between DopaChromeTautomerase and Caveolin-1 is melanoma cell phenotype specific and potentially involved in tumor progression". J Biol Chem., 291: 12481-12500 (2016)
Chiritoiu GN; Jandus C; Munteanu CVA; Ghenea S; Gannon PO; Romero P; Petrescu SM, "Epitope located N-glycans impair the MHC-I epitope generation and presentation" Electrophoresis 37, 1448-1460 (2016)
Ciubotaru M, Surleac MD, Metskas LA, Koo P, Rhoades E, Petrescu A-J, Schatz DG., "The architecture of the 12RSS in V(D)J recombination signal and synaptic complexes" Nucleic Acid Res, 43, 917–931 (2015)
Sueldo DJ, Shimels M, Spiridon LN, Caldararu O, Petrescu AJ, Joosten MH, Tameling WI., "Random mutagenesis of the nucleotide-binding domain of NRC1 (NB-LRR Required for Hypersensitive Response-Associated Cell Death-1), a downstream signalling nucleotide-binding, leucine-rich repeat (NB-LRR) protein, identifies gain-of-function mutations in the nucleotide-binding pocket.", New Phytol. 208, 210-223 (2015)
Zhang YH, Shetty K, Surleac MD, Petrescu AJ, Schatz DG. "Mapping and Quantitation of the Interaction between the Recombination Activating Gene Proteins RAG1 and RAG2.", J.Biol.Chem. 290, 11802-17. (2015)
Sarbu M, Munteanu CVA, Dehelean L, Petrescu AJ, Jasna PK, Zamfir AD, "Identification and structural characterization of novel O- and N-glycoforms in the urine of a Schindler disease patient by Orbitrap mass spectrometry" J.Mass.Spectrometry, 50, 1044-1056 (2015)
Robu AC; Popescu L; Munteanu CVA; Seidler DG; Zamfir AD, "Orbitrap mass spectrometry characterization of hybrid chondroitin/dermatan sulfate hexasaccharide domains expressed in brain" Anal.Biochem. 485, 122-131 (2015)
Tanase CI; Draghici C; Shova S; Cojocaru A; Maganu M; Munteanu CVA; Cocu F, "Regioselective reactions on a 1,3-disubstituted dihydroxymethyl or dicarboxyl hexahydropentalene skeleton" Tetrahedron 71, 6852-6859 (2015)
Tanase CI; Draghici C; Caproiu MT; Shova S; Cojocaru A; Munteanu CVA, "MCPB treatment of (+/-)-(1 alpha,3 alpha,3a beta,6a beta)-1,2,3,3a,4,6a-hexahydro-1,3-pentalenedimethanol and its O-acyl-protected derivatives; X-ray crystallography" Tetrahedron 71, 4154-4162 (2015)
Avram S, Borcan F, Borcan LC, Milac AL, Mihailescu D. "QSAR Approaches Applied to Anti-depressants Induced Neurogenesis--in vivo and in silico Applications". Mini Rev Med Chem., 16: 230-240 (2015)
Milac AL, Bojarska E and Wypijewska del Nogal A “Decapping Scavenger (DcpS) enzyme: Advances in its structure, activity and roles in the cap-dependent mRNA metabolism”, BBA-Gene Reg.Mech. 1839: 452-462 (2014)
Sela H, Spiridon LN, Ashkenazi H, Bhullar NK, Brunner S, Petrescu A-J, Fahima T, Keller B, Jordan T, "3D modeling and diversity analysis reveals distinct AVR recognition sites and evolutionary pathways in wild and domesticated wheat Pm3 R genes" Mol Plant Microbe Interact., 27, 835-845 (2014)
Filimon A, Zurac SA, Milac AL, Sima LE, Petrescu SM, Negroiu G. "Value of Dopachrome tautomerase (DCT) in the assessment of melanocytic tumors", Melanoma Res. 24: 219-236 (2014)
Buiu C, Avram S, Duda-Seiman D, Milac AL, Duda-Seiman C, Pacureanu L, Borcan F, "More Effective DPP4 Inhibitors as Antidiabetics Based on Sitagliptin Applied QSAR and Clinical Methods" Current Computer-Aided Drug Design, 10:237-49 (2014)
Avram S, Milac AL, Mernea M, Mihailescu D, Putz MV, Buiu C, “Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants–new opportunity for the genetic disorders control”, International Journal of Molecular Sciences;15:21381-400 (2014)
Avram S, Milac A, Buiu C, Borcan LC, “Advanced QSAR and Computational Mutagenesis Applied To Mitotic Checkpoint Protein Hmad1 Mutants With Implication In Genetic Disorders” New Frontiers in Chemistry, 23:61-72 (2014)
Petrareanu G; Balasu MC; Vacaru AM; Munteanu CVA; Ionescu AE; Matei I; Szedlacsek SE, "Phosphoketolases from Lactococcus lactis, Leuconostoc mesenteroides and Pseudomonas aeruginosa: dissimilar sequences, similar substrates but distinct enzymatic characteristics" Appli.Microb.Biotech. 98, 7855-7867 (2014)
Ciubotaru M, Trexler AJ, Spiridon LN, Surleac MD, Rhoades E, Petrescu AJ, Schatz DG. " RAG and HMGB1 create a large bend in the 23RSS in the V(D)J recombination synaptic complexes.", Nucl.Acid.Res., 41, 2437-2425 (2013)
Slootweg EJ, Spiridon LN, Roosien J, Butterbach P, Pomp R, Westerhof L, Wilbers R, Bakker E, Bakker J, Petrescu A-J, Smant G, Goverse A "Structural Determinants at the Interface of the ARC2 and LRR Domains Control the Activation of the NB-LRR Plant Immune Receptors Rx1 and Gpa2.", Plant Physiol., 161(3), 1510-1528 (2013)
Wypijewska del Nogal A, Surleac M, Kowalska J, Łukaszewicz M, Jemielity J, Bisaillon M, Darżynkiewicz E, Milac AL, Bojarska E. “Analysis of Decapping Scavenger (DcpS)-cap complex using modified cap analogs reveals molecular determinants for efficient cap binding” FEBS J., 280(24): 6508-6527 (2013)
Flangea C, Petrescu A-J, Seidler DG, Munteanu CVA, Zamfir AD, "Identification of an unusually sulfated tetrasaccharide chondroitin/dermatan motif in mouse brain by combining chip- nanoelectrospray multistage MS2-MS4 and high resolution mass spectrometry.", Electrophoresis, 34(11), 1581-1592 (2013)
Zamfir AD; Fabris D; Capitan F; Munteanu CVA; Vukelic Z; Flangea C, Profiling and sequence analysis of gangliosides in human astrocytoma by high-resolution mass spectrometry Anal.Bioanal.Chem. 405(23), 7321-7335 (2013)
Florian PE, Macovei A, Lazar C, Milac AL, Sokolowska I, Darie CC, Evans RW, Roseanu A, Branza-Nichita N. “Characterization of the anti-HBV activity of lactoferrin-1 derived peptides”, Journal of Medical Virology, 85(5): 780-788 (2013)
Avram S, Milac AL, Carta F, Supuran CT. “More effective dithiocarbamates derivatives inhibiting carbonic anhydrases, generated by QSAR and computational design”, J.Enz.Inhib.Med.Chem., 28(2): 350-359 (2013)
Sela H, Spiridon LN, Petrescu A-J, Akerman M, Mandel-Gutfreund Y, Nevo E, Loutre C, Keller B, Schulman AH, Fahima T, "Ancient diversity of splicing motifs and protein surfaces in the wild emmer wheat (Triticum dicoccoides) LR10 coiled coil (CC) and leucine-rich repeat (LRR) domains" Mol. Plant Pathol, 13(3), 276–287 (2012)
Marin BM, Ghenea S, Spiridon LN, Chiritoiu GN, Petrescu AJ, Petrescu SM, " Tyrosinase Degradation Is Prevented when EDEM1 Lacks the Intrinsically Disordered Region.", PloS One, 7(8), e42998 (2012)
Avram S, Milac AL, Mihailescu D. “3D-QSAR study indicates an enhancing effect of membrane ions on psychiatric drugs targeting serotonin receptor 5-HT1A”, Mol.BioSyst. 8(5): 1418 - 1425 (2012)
Avram S, Mihailescu D, Borcan F, Milac AL. "Prediction of improved antimicrobial mastoparan derivatives by 3D-QSAR-CoMSIA/CoMFA and computational mutagenesis", Monatshefte für Chemie - Chemical Monthly. 143(4): 535-543 (2012)
Avram S, Buiu C, Borcan F and Milac AL, "More effective antimicrobial mastoparan derivatives, generated by 3D QSAR-Almond and computational mutagenesis", Mol. BioSyst., 8(2):587-594 (2012).
Maekawa T, Cheng W, Spiridon LN, Töller A, Lukasik E, Saijo Y, Liu P, Shen Q-H, Micluta MA, Somssich IE, Takken FLW, Petrescu A-J, Chai J, Schulze-Lefert P, "Coiled-coil domain-dependent homodimerization of intracellular MLA immune receptors defines a minimal functional module for triggering cell death", Cell Host-Microbe, 9(3), 187-199 (2011)
Cioaca D, Ghenea S, Spiridon LN, Marin M, Petrescu AJ, Petrescu SM. "C-terminus glycans with critical functional role in the maturation of secretory glycoproteins." PLoS One. 6(5), e19979 (2011)
Grozav AG, Willard BB, Kozuki T, Chikamori K, Micluta MA, Petrescu A-J, Kinter M, Ganapathi R, Ganapathi MK. “Tyrosine 656 in topoisomerase IIß is important for the catalytic activity of the enzyme: Identification based on artifactual +80-Da modification at this site”. Proteomics. 11(5), 829-842 (2011)
Milac AL, Anishkin A, Fatakia SN, Chow CC, Sukharev S. and Guy HR, “Structural Models of TREK Channels and their Gating Mechanism”, Channels (Austin), 5(1):23-33 (2011)
Maksaev G, Milac AL, Anishkin A, Guy HR, Sukharev S., “Analyses of gating thermodynamics and effects of deletions in the mechanosensitive channel TREK-1: comparisons with structural models”, Channels (Austin): 5(1):34-42 (2011).
Slootweg E, Roosien J, Spiridon LN, Petrescu A-J, Tameling W, Joosten M, Pomp R, vanSchaik C, Borst JW, Smant G, Schots A, Bakker J, Goverse A. "Nucleocytoplasmic Distribution is Required for Activation of Resistance by the Potato NB-LRR Receptor Rx1 and is Balanced by its Functional Domains.", Plant Cell, 22(12): 4195-4215 (2010)
Anishkin A, Milac AL, Guy HR "Symmetry-restrained molecular dynamics simulations improve homology models of potassium channels.", Proteins, 78(4), 932-949 (2010)
Balasu MC, Spiridon LN, Miron S, Craescu CT, Scheidig AJ, Petrescu AJ, Szedlacsek SE. "Interface analysis of the complex between ERK2 and PTP-SL.", PLoS One, 4(5), e5432 (2009)
Rehman S, Postma W, Tytgat T, Prins P, Qin L, Overmars H, Vossen J, Spiridon LN, Petrescu A-J, Goverse A, Bakker J, Smant G."A Secreted SPRY domain-containing protein (SPRYSEC) from the plant-parasitic nematode Globodera rostochiensis interacts with a CC-NB-LRR protein from a susceptible tomato.", Mol.Plant.Microbe.Interact., 23 (3), 330-340 (2009)
Kammenga JE, Doroszuk A, Riksen JA, Hazendonk E, Spiridon L, Petrescu A-J, Tijsterman M, Plasterk RH, Bakker J "A Caenorhabditis elegans wild type defies the temperature-size rule owing to a single nucleotide polymorphism in tra-3.", PLoS Genet. 3(3), e34 (2007)
Kudla U, Milac AL, Qin L, Overmars H,..., Petrescu A-J, Goverse A, Bakker J, Helder J, Smant G "Structural and functional characterization of a novel, host penetration-related pectate lyase from the potato cyst nematode Globodera R", Mol.Plant Pathol, 8(3), 293-305 (2007)
Petrescu A-J, Wormald MR, Dwek RA., "Structural aspects of glycomes with a focus on N-glycosylation and glycoprotein folding.", Curr Opin Struct Biol, 16, 600-607 (2006)
Paduraru C, Spiridon L, Yuan W, Bricard G, Valencia X, Porcelli S, Illarionov P, Besra G, Petrescu SM, Petrescu A-J, Cresswell P. "An N-linked glycan modulates the interaction between the CD1d heavy chain and beta 2-microglobulin.", J Biol Chem., 281(52), 40369-78 (2006)
Milac AL, Avram S, Petrescu A-J, "Evaluation of a neural networks QSAR method based on ligand representation using substituent descriptors Application to HIV-1 protease inhibitors." J Mol Graph Model. 25, 37-45 (2006)
Costin GE, Valencia JC, Wakamatsu K, Solano F, Milac AL, Vieira WD, Petrescu A-J, Lamoreux ML, Hearing VJ, "Mutations in dopachrome tautomerase (Dct) affect eumelanin/pheomelanin synthesis, but do not affect intracellular trafficking of the mutant protein", Biochem. J., 391, 249-259 (2005)
Kudla U, Qin L, Milac AL, Kielak A, Maissen C, Overmars H, Popeijus H, Roye E, Petrescu A-J, Smant G, Helder L, "Origin, distribution and 3D/modelling of Gr/EXP1, an expansin from the potato cyst nematode Globodera rostochiensis", FEBS Lett, 579, 2451-2457 (2005)
Jaubert S, Milac AL, Petrescu A-J, Almeida J, Abad P, Rosso M-N, "In Planta Secretion of a Calreticulin by Migratory and Sedentary Stages of Root-Knot Nematode", Mol.Plant-Microbe Int., 18, 1277-1284 (2005)
Avram S, Milac AL, Flonta M-L "Computer-Aided Drug Design for Typical and Atypical Antipsychotic Drugs " Curr.Comp.Aid.Drug.Des., 1(4), 347-364 (2005)
Petrescu A-J, Milac AL, Petrescu SM, Dwek RA, Wormald MR, "Statistical analysis of the protein core around N-glycosylation sites. Implications on occupancy, folding and function", Glycobiology 14: 103-114 (2004)
Petrescu SM, Popescu CI, Petrescu A-J, Dwek RA, "The Glycosylation of Tyrosinase in Melanoma Cells and the Effect on Antigen Presentation", Glycobiology and Medicine, Axford J.S. (ed), Kluwer Academic, Adv.Exp.Med.Biol, 535, 257-269 (2003)
Wormald M., Petrescu A.J., PaoY-L., Glythero A., Elliot T., Dwek R.A. "Conformational Studies of Oligosacharides and Glycopeptides : Complementarity of NMR, X-Ray Crystallography and Molecular Modelling", Chem.Rev., 102: 371-387 (2002)
Hinsen K, Petrescu A-J, Dellerue S, Belissent-Funel MC, Kneller GR – "Liquid-like and solid-like motions in proteins", J.Mol. Liquids, 98-99, 381-398 (2002)
Delerue S, Petrescu A-J, Smith JC, Bellisent-Funel MC, “Radially softening diffusive motions in a globular protein”, Biophys. J., 81, 1666-1676 (2001)
Branza-Nichita N, Petrescu A-J, Negroiu G, Dwek RA, Petrescu SM, "N-glycosylation Processing and Glycoprotein Folding – Lessons from the TRPs", Chem Rev, 100, 4697-4711 (2000)
Branza-Nichita N, Negroiu G, Petrescu AJ, Garman EF, Platt F, Wormald M, Dwek RA, Petrescu SM, “Mutations at Critical N-Glycosylation Sites Reduce Tyrosinase Activity by Altering Quality Control", J.Biol.Chem., 275, 8169-8175 (2000)
Petrescu SM, Branza-Nichita N, Negroiu G, Petrescu AJ, Dwek RA, "Tyrosinase and Glycoprotein Folding : Roles of Chaperones That Recognize Glycans", Biochemistry, 39, 5229-5237 (2000)
Petrescu SM, Petrescu A-J, Platt FM, Dwek RA, “Glycosylation and Glycoprotein Folding", Wellcome Trust Reviews, 41-42 (2000)
Petrescu A-J, Calmettes P, Durand D, Receveur V, Smith JC, “Change in Backbone Torsion Angle Distribution on Protein Folding", Protein Sci., 9, 1129-36 (2000)
Dellerue S, Petrescu A-J, Smith JC, Longeville S, Bellissent-Funel M-C,"Collective Dynamics of a Photosyntethic Protein Probed by Neutron Spin-Echo Spectroscopy and Molecular Dynamics Simulation", Physica B., 276-278, 514-515 (2000)
Hinsen K, Petrescu A-J, Delerue S, Bellissent-Funel M-C, Kueller GR, “Harmonicity in slow protein dynamics", Chem.Phys., 261, 25-37 (2000)
Petrescu A-J, Petrescu SM, Dwek RA, Wormald MR,"A Statistical Analysis of N- and O-glycan linkage conformations from crystallographyc data", Glycobiology, 9, 343-352 (1999)
Nichita-Branza N, Petrescu A-J, Dwek RA, Wormald M, Platt F, Petrescu S-M,"Tyrosinase folding and copper loading in vivo: a crucial role for calnexin and a-glucosidase II" Biochem. Biophys. Res. Commun., 261, 720-725 (1999)
Negroiu G, Branza-Nichita N, Petrescu A-J, Dwek RA, Petrescu S-M"Protein specific N-glycosylation of tyrosinase and TRP-1 in B16 F1 mouse melanoma cells", Biochem. J., 344, 659-665 (1999)
Negroiu G, Branza-Nichita N, Costin G, Titu H, Petrescu A-J, Dwek RA, Petrescu S-M, "Investigation of the Intracellular Transport of Tyrosinase and TRP-1 the effect of the ER Glucosidases Inhibition" Mol.Cell.Biol, 45, 1001-1010 (1999)
Dellerues S, Petrescu A-J, Smith JC, Longenille S, Bellisent-Funnel MC, "Collective dynamics of a photosintetic protein probed by NES spectroscopy and MD simulation", Physica B, 276-278, 514-515 (1999)
This project aims to address a number of structural aspects related to key elements of the plant immune system and its pathogen interactors using a combined approach intricating experimental and computational steps. To this end we intend to build on our previous results in the field and further develop experimental, bioinformatics and molecular modeling methods appropriate for solving the specific problems implied by this proposal.
A promising approach of the therapeutic strategy in melanoma is immunotherapy. One of the most promising melanoma antigens is tyrosinase, which was frequently found as overexpressed in melanomas. It wash shown that this protein undergoes unproductive folding in the endoplasmic reticulum (ER) leading to the selection of the incorrectly folded molecules for degradation via the ubiquitin proteasome system. The current project aims to obtain epitopes with potential increased clinical outcome.
Databases: SAGS DB - Structural Assesment of Glycosylation Site Database
Simulation Hardware: 1 HP-HPC Cluster (4 TFlop - effective power); 1 Bull-HPC Cluster
Simulation Software: Charmm, Amber, NAMD
Modeling Hardware: 1 HP-Graphic Station ProLiant WS460c; 1 Octane 2x600 SGI Workstation
Modeling Software: Accelrys Discovery Studio, BCI Raptor, Modeller etc