Romanian Society of Biochemistry
Romanian Journal of Biochemistry
IB_Bioinformatics and Structural Biochemistry
Department of Bioinformatics & Structural Biochemistry
Present work and future prospects,
Petrescu Andrei-José, PhD – Head of Department
Robi Tacutu, University of Liverpool, associate fellow
Milac Adina Luminita, Researcher
Micluta Marius, Researcher
Marius Surleac, PhD student
Florin Pastrama, PhD student
Cristian Munteanu, PhD student
Eliza Martin, MSc Student
"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 [6,21,25,32-34,38].
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 [7,18,19,24,26,35].
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 the 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 [27-31,36,37].
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 [2,4,9]; with groups from Universities of Wageningen, Haifa,
Zurich, MPI-Koln, INRA-France etc we are involved in investigating the molecular basis of plant-pathogen
In 2012 Adina Milac joined the DBSB coming from National Institute of Health - NIH Bethesda, USA - bringing in
new research topic related to the structure-function relation in ion-channel systems and drug-design [10,11].
Along the years, DBSB work was financed by a large number of national and international grants such as
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).
The models generated so far in this process allowed us to make predictions upon systems behavior.
Subsequently predictions were successfully proved 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 [1-25].
Present work and furure prospects
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" (2011-2014).
A-JP is Co-PI in the USA-NIH grant 4R37 AI032524 "Structure of RAG1-RAG2-DNA complexes"
and member of the MC of COST Action "Sustain" FA1208-11941: "
Pathogen-informed strategies for sustainable broad-spectrum crop resistance" (2013-2016).
We have ongoing projects to developing new statistical and machine learning techniques useful in bioinformatics.
Another priority of DBSB 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 .
Starting with 2016 DBSB also hosts a new and exciting research project on the Computational & Sytems Biology of Aging run by
Robi Tacutu, DBSB alumnus and present DBSB associate fellow from the Institute of Integrative Biology of the University
of Liverpool, UK
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
|"The architecture of the 12RSS in V(D)J recombination signal and synaptic complexes.",
Nucl.Acid.Res., 43(2), 917-931 (2015)
Ciubotaru M, Surleac MD, Metskas LA, Koo P, Rhoades E, Petrescu AJ, Schatz DG.
|"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),151-1528 (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.
|"RAG and HMGB1 create a large bend in the 23RSS in the V(D)J recombination synaptic complexes.",
Ciubotaru M, Trexler AJ, Spiridon LN, Surleac MD, Rhoades E, Petrescu A-J, Schatz DG.
|"Identification of an unusually sulfated tetrasaccharide chondroitin/dermatan motif in mouse
brain by combining chip- nanoelectrospray multistage MS2-MS4 and high resolution mass spectrometry.",
Flangea C, Petrescu A-J, Seidler DG, Munteanu CVA, Zamfir AD.
|"Analysis of decapping scavenger cap complex using modified cap analogs reveals molecular
determinants for efficient cap binding.",
FEBS J.,280(24), (2013)
Wypijewska Del Nogal A, Surleac MD, Kowalska J, Lukaszewicz M, Jemielity J, Bisaillon M, Darzynkiewicz E, Milac AL, Bojarska E.
|"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.",
Sela H, Spiridon LN, Petrescu A-J, Akerman M, Mandel-Gutfreund Y, Nevo E, Loutre C, Keller B, Schulman AH, Fahima T.
|"Tyrosinase degradation is prevented when EDEM1 lacks the intrinsically disordered region.",
PLoS One.,7(8), e42998 (2012)
Marin MB, Ghenea S, Spiridon LN, Chiritoiu GN, Petrescu A-J, Petrescu SM.
|"C-terminus glycans with critical functional role in the maturation of secretory glycoproteins.",
PLoS One.,6(5),e19979 (2011)
Cioaca D, Ghenea S, Spiridon LN, Marin M, Petrescu AJ, Petrescu SM.
|"A Caenorhabditis elegans wild type defies the temperature-size rule owing to a
single nucleotide polymorphism in tra-3.",
Cell Host & Microbe., 9(3), 187-199 (2011)
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.
|"Tyrosine 656 in topoisomerase II. 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)
Grozav AG, Willard BB, Kozuki T, Chikamori K, Micluta MA, Petrescu A-J, Kinter M, Ganapathi R.
|"Structural models of TREK channels and their gating mechanism.",
Channels (Austin).,5(1), 23-33 (2011)
Milac A, Anishkin A, Fatakia SN, Chow CC, Sukharev S, Guy HR.
|"Symmetry-restrained molecular dynamics simulations improve homology
models of potassium channels.",
Proteins.,78(4), 932-949 (2010)
Anishkin A, Milac AL, Guy HR.
|"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)
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.
|"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..,22(3),330-340 (2009)
Postma W, Tytgat T, Prins P, Qin L, Overmars H, Vossen J, Spiridon L, Petrescu AJ, Goverse A, Bakker J, Smant G, Rehman S.
|"Interface analysis of the complex between ERK2 and PTP-SL.",
PLoS One.,4(5),e5432 (2009)
Balasu MC, Spiridon LN, Miron S, Craescu CT, Scheidig AJ, Petrescu AJ, Szedlacsek SE.
|"Structural and functional characterization of a novel, host penetration-related pectate lyase
from the potato cyst nematode Globodera rostochiensis",
Mol. Plant Pathol.,8(3),293-305 (2007)
Kudla U, Milac AL, Qin L, Overmars H, Roze E, Holterman M, Petrescu A-J, Goverse A, Bakker J, Helder J, Smant G
|"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)
Kammenga JE, Doroszuk A, Riksen JA, Hazendonk E, Spiridon L, Petrescu A-J, Tijsterman M, Plasterk RH, Bakker J.
|"Structural and functional characterization of a novel, host penetration-related pectate lyase from the potato cyst nematode Globodera rostochiensis.",
Mol Plant Pathol.,8(3),293-305 (2007)
Kudla U, Milac AL, Qin L, Overmars H, Roze E, Holterman M, Petrescu A-J, Goverse A, Bakker J, Helder J, Smant G.
|"An N-linked glycan modulates the interaction between the CD1d heavy chain and beta 2-microglobulin.",
J Biol Chem.,281(52), 40369-40378 (2006)
Paduraru C, Spiridon L, Yuan W, Bricard G, Valencia X, Porcelli S, Illarionov P, Besra G, Petrescu SM, Petrescu A-J, Cresswell P.
|"Structural aspects of glycomes with a focus on N-glycosylation and glycoprotein folding.",
Curr Opin Struct Biol.,16(5),600-607 (2006)
Petrescu A-J, Wormald MR, Dwek RA.
|"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(1),37-45 (2006)
Milac AL, Avram S, Petrescu A-J.
|"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)
Costin GE, Valencia JC, Wakamatsu K, Ito S, Solano F, Milac A-L, Vieira WD, Yamaguchi Y, Rouzaud F, Petrescu A-J, Lamoreux ML, Hearing VJ.
|"Origin, distribution and 3D-modelling of Gr-EXP1, an expansin from the potato cyst nematode Globodera rostochiensis", FEBS Lett,
579, 2451-2457 (2005)
Kudla U, Qin L, Milac A-L, Kielak A, Maissen C, Overmars H, Popeijus H, Roze E, Petrescu A-J, Smant G, Bakker J, Helder J.
|"In Planta Secretion of a Calreticulin by Migratory and Sedentary Stages of Root-Knot Nematode", Mol. Plant-Microbe Int.,
18, 1277-1284 (2005)
Jaubert S, Milac A-L, Petrescu A-J, de Almeida-Engler J, Abad P, Rosso M-N.
|"Statistical analysis of the protein environment
of N-glycosylation sites: implications for occupancy, structure, and folding.", Glycobiology.
14: 103-114 (2004)
Petrescu A-J, Milac AL, Petrescu SM, Dwek RA, Wormald MR.
|"The glycosylation of tyrosinase in melanoma
cells and the effect on antigen presentation.", Adv.Exp.Med.Biol.;
535, 257-269 (2003)
Petrescu SM, Popescu CI, Petrescu A-J, Dwek RA.
|"Conformational Studies of Oligosacharides and
Glycopeptides: Complementarity of NMR, X-Ray Crystallogrphy and Molecular
Modelling", Chem.Rev., 102, 371-387 (2002)
Wormald M, Petrescu A-J, Pao Y-L, Glythero A, Elliot T, Dwek RA
|“Liquid-like and solid-like motions in proteins”,
J.Mol. Liquids, 98-99, 381-398 (2002)
Hinsen K, Petrescu A-J, Dellerue S, Belissent-Funel MC, Kneller, GR
|"Radially softening diffusive motions in a globular
protein." Biophys. J., 81, 1666-1676 (2001)
Dellerue S, Petrescu A-J, Smith JC, Bellissent-Funel MC
|"Collective dynamics of a photosynthetic protein
probed by neutron spin-echo spectroscopy and molecular dynamics simulation"Physica
B , 276-278, 514-515 (2000)
Dellerue S, Petrescu A-J, Smith JC, Longeville S, Bellissent-Funel M-C
|"Harmonicity in slow protein dynamics", Chem.Phys.
261, 25-37 (2000)
Hinsen K, Petrescu A-J, Dellerue S, Bellissent-Funel M-C. & Kneller
|"Change in backbone torsion angle distribution
on protein folding" Protein Sci., 9, 1129-36 (2000)
Petrescu A-J, Calmettes P, Durand D, Receveur V, Smith JC
|"N-glycosylation processing and glycoprotein
folding-lessons from the tyrosinase- related proteins", Chem. Rev.,
100, 4697-4711 (2000)
Branza-Nichita N., Petrescu A-J, Negroiu G., Dwek RA., Petrescu SM
|"Tyrosinase and Glycoprotein Folding", Biochemistry
39, 5229-5237 (2000)
Petrescu SM, Branza-Nichita N, Negroiu G, Petrescu A-J, Dwek RA
|"Mutations at Critical N-Glycosylation Sites
Reduce Tyrosinase Activity by Altering Folding and Quality Control",
J.Biol.Chem., 275, 8169-8175 (2000)
Branza-Nichita N, Negroiu G, Petrescu A-J, Garman EF, Platt FM, Wormald
M, Dwek RA, Petrescu S.M.
|"A Statistical Analysis of N- and O-glycan linkage
conformations from crystallographyc data" Glycobiology,
9, 343-352 (1999)
Petrescu A-J, Petrescu SM, Dwek RA, Wormald MR
|"Excluded Volume in the Configurational Distribution
of a Strongly Denatured Protein", Protein. Sci., 7,1396-1403,
Petrescu A-J, Calmettes P, Receveur V., Durand D., Smith J
|"Small Angle Neutron Scattering By a Strongly
Denatured Protein: Analysis using Random Polymer Theory", Biophysical
J., 72, 335-342 (1997)
Petrescu A-J, Receveur V, Calmettes P, Durand D, Desmadril M, Roux B, Smith
"The Solution NMR Structure of Glc3Man9 unit in Glc3Man7GlcNAc2",
EMBO J., 16, 4302-4310 (1997)
Petrescu A-J, Butters TD, Reinkensmeier G, Petrescu SM, Platt FM, Dwek RA,
Lectures in Molecular Biophysics