Leherte, Laurence

Vercauteren, Daniel

English

To model and simulate large molecular systems like proteins, the development of reduced representations is currently an active field of research. In a previous work [1], we developed an approach to locate minima and maxima in a smoothed charge density field ρsm calculated through the Poisson equation:  where Φsm is the corresponding smoothed molecular electrostatic potential (MEP) built from a set of atomic charges [2]. More particularly, the approach has been applied to the design of amino acid (AA) reduced point charge models (Figure). The AA models allow to reproduce protein MEP maps, and additionally, provide solvation free energies obtained using the program APBS [3] that are in good agreement, when all-atom molecular surfaces are used, with the all-atom ones. The new charges and interaction parameters have additionally been implemented in the program TINKER [4] to carry out molecular dynamics simulations of polypeptides [5]. Reduced point charge model of triptophan as obtained from a smoothed Amber99-based charge density distribution function.References:1. Leherte, L., Vercauteren, D.P. J. Comput.-Aided Mol. Des., 25 (2011) 913-930.2. Leherte, L., Vercauteren, D.P. J. Chem. Theory Comput., 5 (2009) 3279-3298.3. Baker, N.A., Sept, D., Joseph, S., Holst, M.J., McCammon, J.A. Proc. Natl. Acad. Sci. USA, 98 (2001) 10037-10041.4. TINKER - Software Tools for Molecular Design, http://dasher.wustl.edu/tinker/5. Leherte, L., Vercauteren, D.P. J. Phys. Chem. A, 115 (2011) 12531-12543.<br/

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RESEARCH OUTPUTS / RÉSULTATS DE RECHERCHEAuthor(s) - Auteur(s) :Publication date - Date de publication :Permanent link - Permalien :Rights / License - Licence de droit d’auteur :Bibliothèque Universitaire Moretus PlantinInstitutional Repository - Research PortalDépôt Institutionnel - Portail de la Rechercheresearchportal.unamur.beDesign of a reduced point charge model for proteins – Molecular DynamicsapplicationsLeherte, Laurence; Vercauteren, DanielPublication date:2012Document VersionPeer reviewed versionLink t  publicationCitation for pulished version (HARVARD):Leherte, L & Vercauteren, D 2012, 'Design of a reduced point charge model for proteins – Molecular Dynamicsapplications', Quantum Chemistry in Belgium X, Brussels, Belgium, 10/02/12 - 10/02/12.General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 23. Jun. 2020Coilβ-sheetβ-bridgeBendTurn1. Ubiquitin protein-ligase Nedd4-2 (PDB access code 1WR3) The positioning of CGs is achieved with QUATFIT [9], a superposition algorithm,using the amino acid templates and the PDB structures of the proteins. End positive and negative charges (± 0.929 e-) are added on terminal N and OXTatoms.2. Isocontours of the electrostatic potential (-0.05, 0.05 e-/bohr)3. Implementation4. Results0.80.91.00 20 40 60 80 100 120 140 160 180 200DACF(t)t (ps)01234560 1000 2000 3000 4000 5000msd (Å2 )t (ps)Design of a reduced point charge model for proteins: Molecular Dynamics ApplicationsLaurence Leherte, Daniel P. Vercauteren - University of Namur - Belgium (FUNDP)This work is part of a more general project on multiresolution analysis of three-dimensional (3D) molecular fields. More specifically, it is related to thetopolographical analysis of smoothed charge density (CD) distribution functions.From such functions, we show how to obtain a reduced point charge model (alsonamed here coarse grain (CG) model) for proteins and we assess the applicability tomolecular dynamics (MD) simulations of protein structures.Framework1. Smoothed Charge Density2. Location of CGs in ρA,tA hierarchical merging algorithm, based on the idea of Leung et al. [5], is used tolocate local extrema in ρA,t. At scale t = 0, each atom of a molecular structure is considered as astarting point of the merging procedure. As t increases, each point moves along a gradient path to reach a locationin the 3D space whereThese trajectories are defined by:3. Backbone CGsa. An extended strand β-Gly15 is built considering (Ω = 180°, Φ = -139°, Ψ = 135°)using the program SMMP05 [5].b. Atomic charges are assigned using PDB2PQR [2].c. The merging/clustering program is then applied separately to negative andpositive charges of β-Gly15. The central motif is isolated and further used astemplate for the backbone of any amino acid residue (see Figure below).4. Side Chain CGsa. Each isolated amino acid is considered with various conformations [6] builtusing SMMP05 [5].b. Atomic charges are then assigned using PDB2PQR [2].c. CGs are finally obtained using the merging/clustering program.5. Charge FittingIt is achieved with the program QFIT [7] to get CG point charges fitted from anunsmoothed electrostatic potential grid, considering the various rotamers with twoconstraints: molecular charge and dipole.Charges are assigned in two steps. First, side chain CGs are treated. Second,backbone charges are adjusted while keeping the side chain charges to their pre-determined values.Templates are thus obtained for each amino acid residue [8]. For instance:∑∈ −=Aa aaARrqrV rrr)(∑∈ −−=AaaaatAtRrerfRrqrV2)(,rrrrrUnsmoothed electrostatic Coulomb potentialgenerated by molecule A.  Amber99 atomiccharges [1] are assigned to atoms using PDB2PQR [2].Smoothed electrostatic potential [3]Poisson Equation  Smoothed CD ρA,t(t = smoothing degree)0,,2ερ tAtAV =∇−0,=∇ tAρrtAtAttAtArr,,,,ρρρρ∇∆+=∆−rrrΔ = displacement stepReduced Point Charge Model( )tratA etq 422/3, 4−=piρ Analytical expression of ρA,tMolecular Dynamics ApplicationsAll-atom CG(1) Wang et al., J Comput Chem 21 (2000) 1049 (2) pdb2pqr.sourceforge.net (3) Amara & Straub, PhysRev B 53 (1996) 13857 (4) Leung et al. IEEE T Pattern Anal 22 (2000) 1396 (5) Eisenmenger et al.Comp Phys Comm 174 (2006) 422, www.smmp05.net (6) Simms et al., Prot Eng Des Select 21 (2008)369, www.dynameomics.org (7) Borodin et al. Force Field Fitting Toolkit,www.eng.utah.edu/~gdsmith/fff.html (8) Leherte & Vercauteren, J Comput Aided Mol Des 25 (2011)913 (9) Heisterberg, Ohio Supercomputer Center, translation from FORTRAN to C and Input/Outputby Labanowski, 1990 (10) Leherte & Vercauteren, J Phys Chem A 115 (2011) 12531 (11) TINKER -Software Tools for Molecular Design, http://dasher.wustl.edu/tinker/Gly-Hisδ-Gly10 ns (107 x 1 fs)T = 298 KVacuumCPU time AA/CG = 2000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000005101520253035ResidueTime (ps)Secondary structureCoil B-Sheet B-Bridge Bend TurnAll-atom CGDSSP secondary structures: Only the mainfeatures of the secondary structure arepreserved in the CG simulation.Isocontours of the CD: -0.005, +0.005 e- bohr-3.781.281-.788.080-.35436 aa / 577 atoms / 158 point charges or CGs (white spheres) [10]The new set of charges was implemented inthe program TINKER [11]. The fact thatthe point charges are not necessarilylocated on atoms makes the implementationchallenging and, as a first trial, the originalcode was not modified. Thus, the chargesare treated as additional particles (m = 2)held together and to heavy atoms of themolecular structure by harmonic bonds [10].Snapshots at 10 nsAll-atomCGCristal structurePDB01230 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000rmsd (Å)t (ps)Dipole autocorrelation functionrmsd(t)01231 6 11 16 21 26 31 36rmsd (Å)Amino acid #Mean Cα rmsdMean square displacementCG locations and number are determined only from the topography of the CDdistribution functions.Charge centers differ from atom centers  challenge for MD applications.Some secondary structure elements are preserved vs. the all-atom model as well asthe global fold of the peptide.Dynamical results are in agreement with the all-atom ones, but the mean squaredisplacement is reduced.One also observes an increased conformational stability of the CG model.As a perspective, we are considering the instantaneous update of the CG model duringthe MD simulation (to avoid to assign a mass to the CGs).ConclusionsAll-atomCG000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000005101520253035ResidueTime (ps)Coil B-Sheet B-Bridge Bend Turn 3-HelixGly-Hisδ-Gly HisδRéférences

Design of a reduced point charge model for proteins – Molecular Dynamics applications

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Design of a reduced point charge model for proteins – Molecular Dynamics applications

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