Publications (129)375.93 Total impact

Article: The elusive quest for RNA knots
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ABSTRACT: Physical entanglement, and particularly knots arise spontaneously in equilibrated polymers that are sufficiently long and densely packed. Biopolymers are no exceptions: knots have long been known to occur in proteins as well as in encapsidated viral DNA. The rapidly growing number of RNA structures has recently made it possible to investigate the incidence of physical knots in this type of biomolecule, too. Strikingly, no knots have been found to date in the known RNA structures. In this Point of View Article we discuss the absence of knots in currently available RNAs and consider the reasons why knots in RNA have not yet been found, despite the expectation that they should exist in Nature. We conclude by singling out a number of RNA sequences that, based on the properties of their predicted secondary structures, are good candidates for knotted RNAs.  [Show abstract] [Hide abstract]
ABSTRACT: Amyloids play a role in the degradation of βcells in diabetes patients. In particular, short amyloid oligomers inject themselves into the membranes of these cells and create pores that disrupt the strictly controlled flow of ions through the membranes. This leads to cell death. Getting rid of the short oligomers either by a deconstruction process or by elongating them into longer fibrils will reduce this toxicity and allow the βcells to live longer. We develop a computational method to probe the binding affinity of amyloid structures and produce an amylin analog that binds to oligomers and extends their length. The binding and extension lower toxicity and βcell death. The amylin analog is designed through a parsimonious selection of mutations and is to be administered with the Pramlintide drug, but not to interact with it. The mutations (T9K L12K S28H T30K) produce a stable native structure, strong binding affinity to oligomers, and long fibrils. We present an extended mathematical model for the insulinglucose relationship and demonstrate how affecting the concentration of oligomers with such analog is strictly coupled with insulin release and βcell fitness. SEMBA, the tool to probe the binding affinity of amyloid proteins and generate the binding affinity scoring matrices and Rscores is available at: http://amyloid.cs.mcgill.ca CONTACT: jeromew@cs.mcgill.ca. © The Author (2015). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.  [Show abstract] [Hide abstract]
ABSTRACT: We propose a novel stochastic method to exactly generate Brownian paths conditioned to start at an initial point and end at a given final point during a fixed time $t_{f}$. These paths are weighted with a probability given by the overdamped Langevin dynamics. We show how these paths can be exactly generated by a local stochastic differential equation. The method is illustrated on the generation of Brownian bridges, Brownian meanders, Brownian excursions and constrained OrnsteinUehlenbeck processes. In addition, we show how to solve this equation in the case of a general force acting on the particle. As an example, we show how to generate constrained path joining the two minima of a doublewell. Our method allows to generate statistically independent paths, and is computationally very efficient.  [Show abstract] [Hide abstract]
ABSTRACT: The ongoing effort to detect and characterize physical entanglement in biopolymers has so far established that knots are present in many globular proteins and also, abound in viral DNA packaged inside bacteriophages. RNA molecules, however, have not yet been systematically screened for the occurrence of physical knots. We have accordingly undertaken the systematic profiling of the several thousand RNA structures present in the Protein Data Bank (PDB). The search identified no more than three deeply knotted RNA molecules. These entries are rRNAs of about 3,000 nt solved by cryoEM. Their genuine knotted state is, however, doubtful based on the detailed structural comparison with homologs of higher resolution, which are all unknotted. Compared with the case of proteins and viral DNA, the observed incidence of knots in available RNA structures is, therefore, practically negligible. This fact suggests that either evolutionary selection or thermodynamic and kinetic folding mechanisms act toward minimizing the entanglement of RNA to an extent that is unparalleled by other types of biomolecules. A possible general strategy for designing synthetic RNA sequences capable of selftying in a twistknot fold is finally proposed.  [Show abstract] [Hide abstract]
ABSTRACT: The ongoing effort to detect and characterize physical entanglement in biopolymers has so far established that knots are present in many globular proteins and also abound in viral DNA packaged inside bacteriophages. RNA molecules, on the other hand, have not yet been systematically screened for the occurrence of physical knots. We have accordingly undertaken the systematic profiling of the ~6,000 RNA structures present in the protein data bank. The search identified no more than three deeplyknotted RNA molecules. These are ribosomal RNAs solved by cryoem and consist of about 3,000 nucleotides. Compared to the case of proteins and viral DNA, the observed incidence of RNA knots is therefore practically negligible. This suggests that either evolutionary selection, or thermodynamic and kinetic folding mechanisms act towards minimizing the entanglement of RNA to an extent that is unparalleled by other types of biomolecules. The properties of the three observed RNA knotting patterns provide valuable clues for designing RNA sequences capable of selftying in a twistknot fold. 
Dataset: 161 Adv Mater 2012 24 1952
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ABSTRACT: Methods for computing electrostatic interactions often account implicitly for the solvent, due to the much smaller number of degrees of freedom involved. In the Poisson–Boltzmann (PB) approach the electrostatic potential is obtained by solving the Poisson–Boltzmann equation (PBE), where the solvent region is modeled as a homogeneous medium with a high dielectric constant. PB however is not exempt of problems. It does not take into account for example the sizes of the ions in the atmosphere surrounding the solute, nor does it take into account the inhomogeneous dielectric response of water due to the presence of a highly charged surface. In this paper we review two major modifications of PB that circumvent these problems, namely the sizemodified PB (SMPB) equation and the Dipolar Poisson–Boltzmann Langevin (DPBL) model. In SMPB, steric effects between ions are accounted for with a lattice gas model. In DPBL, the solvent region is no longer modeled as a homogeneous dielectric media but rather as an assembly of selforienting interacting dipoles of variable density. This model results in a dielectric profile that transits smoothly from the solute to the solvent region as well as in a variable solvent density that depends on the charges of the solute. We show successful applications of the DPBL formalism to computing the solvation free energies of isolated ions in water. Further developments of more accurately modified PB models are discussed.  [Show abstract] [Hide abstract]
ABSTRACT: We derive a general meanfield theory of inhomogeneous polymer dynamics; a theory whose form has been speculated and widely applied, but not heretofore derived. Our approach involves a functional integral representation of a MartinSiggiaRose type description of the exact manychain dynamics. A saddle point approximation to the generating functional, involving conditions where the MSR action is stationary with respect to a collective density field $\rho$ and a conjugate MSR response field $\phi$, produces the desired dynamical meanfield theory. Besides clarifying the proper structure of meanfield theory out of equilibrium, our results have implications for numerical studies of polymer dynamics involving hybrid particlefield simulation techniques such as the singlechain in meanfield method (SCMF). 
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ABSTRACT: We introduce a stable and efficient complex Langevin (CL) scheme to enable the first direct numerical simulations of the coherentstates (CS) formulation of polymer field theory. In contrast with Edwards' wellknown auxiliaryfield (AF) framework, the CS formulation does not contain an embedded nonlinear, nonlocal, implicit functional of the auxiliary fields, and the action of the field theory has a fully explicit, semilocal, and finiteorder polynomial character. In the context of a polymer solution model, we demonstrate that the new CSCL dynamical scheme for sampling fluctuations in the space of coherent states yields results in good agreement with nowstandard AFCL simulations. The formalism is potentially applicable to a broad range of polymer architectures and may facilitate systematic generation of trial actions for use in coarsegraining and numerical renormalizationgroup studies. 
Article: Dipolar PoissonBoltzmann Approach to Ionic Solutions: A Mean Field and Loop Expansion Analysis
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ABSTRACT: We study the variation of the dielectric response of ionic aqueous solutions as function of their ionic strength. The effect of salt on the dielectric constant appears through the coupling between ions and dipolar water molecules. On a meanfield level, we account for any internal charge distribution of particles. The dipolar degrees of freedom are added to the ionic ones and result in a generalization of the PoissonBoltzmann (PB) equation called the Dipolar PB (DPB). By looking at the DPB equation around a fixed pointlike ion, a closedform formula for the dielectric constant is obtained. We express the dielectric constant using the "hydration length" that characterizes the hydration shell of dipoles around ions, and thus the strength of the dielectric decrement. The DPB equation is then examined for three additional cases: mixture of solvents, polarizable medium, and ions of finite size. Employing fieldtheoretical methods, we expand the Gibbs freeenergy to first order in a loop expansion and calculate selfconsistently the dielectric constant. For pure water, the dipolar fluctuations represent an important correction to the meanfield value and good agreement with the water dielectric constant is obtained. For ionic solutions we predict analytically the dielectric decrement that depends on the ionic strength in a nonlinear way. Our prediction fits rather well a large range of concentrations for different salts using only one fit parameter related to the size of ions and dipoles. A linear dependence of the dielectric constant on the salt concentration is observed at low salinity, and a noticeable deviation from linearity can be seen for ionic strength above 1 M, in agreement with experiments.  [Show abstract] [Hide abstract]
ABSTRACT: In 1969, Edwards and Freed adapted the ``coherent state'' methods employed in the second quantization formalism of quantum manybody theory to study polymer networks. Since its introduction into polymer science, this formalism has been largely neglected and to our knowledge, has never been applied as a basis for numerical simulations, even for linear polymers. However, in contrast to the Edwards auxiliaryfield framework, this alternative polymer field theory has several attractive features, including an action or effective Hamiltonian with an explicit, finiteorder, and semilocal polynomial character. We thus revisited the CS formalism and show that these characteristics have advantages both for analytical and numerical studies of linear polymers at equilibrium. For this purpose, we developed a new Complex Langevin sampling scheme that allows for simulations within the CS formalism with stable and efficient numerical characteristics. We anticipate that this methodology will facilitate efficient simulations of a wide range of systems, including complicated branched and networked polymers and liquid crystalline polymers.  [Show abstract] [Hide abstract]
ABSTRACT: Amyloid proteins aggregate into polymorphic fibrils that damage tissues of the brain, nerves, and heart. Experimental and computational studies have examined the structural basis and the nucleation of short fibrils, but the ability to predict and precisely quantify the stability of larger aggregates has remained elusive. We established a complete classification of fibril shapes and developed a tool called CreateFibril to build such complex, polymorphic, modular structures automatically. We applied stability landscapes, a technique we developed to reveal reliable fibril structural parameters, to assess fibril stability. CreateFibril constructed HETs, Aβ, and amylin fibrils up to 17 nm in length, and utilized a novel dipolar solvent model that captured the effect of dipoledipole interactions between water and very large molecular systems to assess their aqueous stability. Our results validate experimental data for HETs and Aβ, and suggest novel (to our knowledge) findings for amylin. In particular, we predicted the correct structural parameters (rotation angles, packing distances, hydrogen bond lengths, and helical pitches) for the one and three predominant HETs protofilaments. We reveal and structurally characterize all known Aβ polymorphic fibrils, including structures recently classified as wrapped fibrils. Finally, we elucidate the predominant amylin fibrils and assert that native amylin is more stable than its amyloid form. CreateFibril and a database of all stable polymorphic fibril models we tested, along with their structural energy landscapes, are available at http://amyloid.cs.mcgill.ca.  [Show abstract] [Hide abstract]
ABSTRACT: We present McGenus, an algorithm to predict RNA secondary structures with pseudoknots. The method is based on a classification of RNA structures according to their topological genus. McGenus can treat sequences of up to 1000 bases and performs an advanced stochastic search of their minimum free energy structure allowing for nontrivial pseudoknot topologies. Specifically, McGenus uses a Monte Carlo algorithm with replica exchange for minimizing a general scoring function which includes not only free energy contributions for pair stacking, loop penalties, etc. but also a phenomenological penalty for the genus of the pairing graph. The good performance of the stochastic search strategy was successfully validated against TT2NE which uses the same free energy parametrization and performs exhaustive or partially exhaustive structure search, albeit for much shorter sequences (up to 200 bases). Next, the method was applied to other RNA sets, including an extensive tmRNA database, yielding results that are competitive with existing algorithms. Finally, it is shown that McGenus highlights possible limitations in the free energy scoring function. The algorithm is available as a web server at http://ipht.cea.fr/rna/mcgenus.php.  [Show abstract] [Hide abstract]
ABSTRACT: The generation of defectfree polymer nanostructures by nanoimprinting methods is described. Longrange nanorheology and shorterrange surface energy effects can be efficiently combined to provide alignment of copolymer lamellae over several micrometers. As an example, a perpendicular organization with respect to circular tracks is shown, demonstrating the possibility of writing ordered radial nanostructures over large distances.  [Show abstract] [Hide abstract]
ABSTRACT: We study the variation of the dielectric response of a dielectric liquid (e.g. water) when a salt is added to the solution. Employing fieldtheoretical methods we expand the Gibbs freeenergy to first order in a loop expansion and calculate selfconsistently the dielectric constant. We predict analytically the dielectric decrement which depends on the ionic strength in a complex way. Furthermore, a qualitative description of the hydration shell is found and is characterized by a single length scale. Our prediction fits rather well a large range of concentrations for different salts using only one fit parameter related to the size of ions and dipoles.  [Show abstract] [Hide abstract]
ABSTRACT: We study block copolymers (BCP) on patterned substrates, where the top polymer film surface is not constrained but is a free interface that adapts its shape selfconsistently. In particular, we investigate the combined effect of the free interface undulations with the wetting of the BCP film as induced by nanopatterned substrates. For a finite volume of BCP material, we find equilibrium droplets composed of coexisting perpendicular and parallel lamellar domains. The selfassembly of BCP on topographic patterned substrates was also investigated and it was found that the free interface induces mixed morphologies of parallel and perpendicular domains coupled with a nonflat free interface. In both cases, the free interface relaxes the strong constraints that would otherwise be imposed by a fixed top boundary (which is commonly used in simulations), and affects strongly the BCP ordering. Our study has some interesting consequences for experimental setups of graphoepitaxy and nanoimprint lithography.  [Show abstract] [Hide abstract]
ABSTRACT: We present an extension of the selfconsistent mean field theory for protein sidechain modeling in which solvation effects are included based on the PoissonBoltzmann (PB) theory. In this approach, the protein is represented with multiple copies of its side chains. Each copy is assigned a weight that is refined iteratively based on the mean field energy generated by the rest of the protein, until selfconsistency is reached. At each cycle, the variational free energy of the multicopy system is computed; this free energy includes the internal energy of the protein that accounts for vdW and electrostatics interactions and a solvation free energy term that is computed using the PB equation. The method converges in only a few cycles and takes only minutes of central processing unit time on a commodity personal computer. The predicted conformation of each residue is then set to be its copy with the highest weight after convergence. We have tested this method on a database of hundred highly refined NMR structures to circumvent the problems of crystal packing inherent to xray structures. The use of the PBderived solvation free energy significantly improves prediction accuracy for surface side chains. For example, the prediction accuracies for χ(1) for surface cysteine, serine, and threonine residues improve from 68%, 35%, and 43% to 80%, 53%, and 57%, respectively. A comparison with other sidechain prediction algorithms demonstrates that our approach is consistently better in predicting the conformations of exposed side chains.  [Show abstract] [Hide abstract]
ABSTRACT: Small Angle Xray Scattering (SAXS) techniques are becoming more and more useful for structural biologists and biochemists, thanks to better access to dedicated synchrotron beamlines, better detectors and the relative easiness of sample preparation. The ability to compute the theoretical SAXS profile of a given structural model, and to compare this profile with the measured scattering intensity, yields crucial structural informations about the macromolecule under study and/or its complexes in solution. An important contribution to the profile, besides the macromolecule itself and its solventexcluded volume, is the excess density due to the hydration layer. AquaSAXS takes advantage of recently developed methods, such as AquaSol, that give the equilibrium solvent density map around macromolecules, to compute an accurate SAXS/WAXS profile of a given structure and to compare it to the experimental one. Here, we describe the interface architecture and capabilities of the AquaSAXS web server (http://lorentz.dynstr.pasteur.fr/aquasaxs.php).  [Show abstract] [Hide abstract]
ABSTRACT: Loops are essential secondary structure elements in folded DNA and RNA molecules and proliferate close to the melting transition. Using a theory for nucleic acid secondary structures that accounts for the logarithmic entropy c ln m for a loop of length m, we study homopolymeric singlestranded nucleic acid chains under external force and varying temperature. In the thermodynamic limit of a long strand, the chain displays a phase transition between a lowtemperature/lowforce compact (folded) structure and a hightemperature/highforce molten (unfolded) structure. The influence of c on phase diagrams, critical exponents, melting, and force extension curves is derived analytically. For vanishing pulling force, only for the limited range of loop exponents 2 < c ≲ 2.479 a melting transition is possible; for c ≤ 2 the chain is always in the folded phase and for 2.479 ≲ c always in the unfolded phase. A forceinduced melting transition with singular behavior is possible for all loop exponents c < 2.479 and can be observed experimentally by singlemolecule force spectroscopy. These findings have implications for the hybridization or denaturation of doublestranded nucleic acids. The PolandScheraga model for nucleic acid duplex melting does not allow base pairing between nucleotides on the same strand in denatured regions of the double strand. If the sequence allows these intrastrand base pairs, we show that for a realistic loop exponent c ≈ 2.1 pronounced secondary structures appear inside the single strands. This leads to a lower melting temperature of the duplex than predicted by the PolandScheraga model. Further, these secondary structures renormalize the effective loop exponent [Formula: see text], which characterizes the weight of a denatured region of the double strand, and thus affect universal aspects of the duplex melting transition.
Publication Stats
3k  Citations  
375.93  Total Impact Points  
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Institutions

2015

McGill University
 School of Computer Science
Montréal, Quebec, Canada 
Beijing Computational Science Research Center
Peping, Beijing, China


19962014

Cea Leti
Grenoble, RhôneAlpes, France


2012

Scuola Internazionale Superiore di Studi Avanzati di Trieste
 Neurobiology Group
Trst, Friuli Venezia Giulia, Italy


2011

Stanford University
Palo Alto, California, United States 
University of California, Davis
 Department of Computer Science
Davis, California, United States


2010

Atomic Energy and Alternative Energies Commission
 Institut de Physique Théorique (IPhT)
Fontenay, ÎledeFrance, France


2009

French National Centre for Scientific Research
Lutetia Parisorum, ÎledeFrance, France


19982007

University of California, Santa Barbara
 Kavli Institute for Theoretical Physics
Santa Barbara, CA, United States


19941999

Tel Aviv University
 Department of Physics and Astronomy
Tell Afif, Tel Aviv, Israel 
Massachusetts Institute of Technology
 Department of Physics
Cambridge, Massachusetts, United States


19931996

Université de CergyPontoise
95001 CEDEX, IledeFrance, France
