CASLAB ComputerAided Systems Laboratory MOSE Molecular Simulation Engineering

CASLAB: Computer-Aided Systems Laboratory MOSE: Molecular Simulation Engineering Department of Chemical, Environmental and Raw Materials Engineering University of Trieste Piazzale Europa 1, 34127 Trieste (Italy) www. caslab. units. it

Objectives The Computer-Aided-Systems Laboratory (CAS-LAB) is a research structure aiming at developing computer-based techniques for n n design of new molecules for both material and life sciences; property estimation and prediction of materials; investigation of physical chemistry and thermodynamics of life sciences simulation of chemical, biochemical and environmental processes. The primary research objective in such a program is two-fold: n n first, to develop models with a high degree of predictivity for the calculation of thermo physical properties for substances, including the molecular design of chemical compounds of interest in material and life sciences; second, to investigate their application to the synthesis, design and control of chemical processes, as well as to organize the information in data bases and distribute them to the scientific community. CASLAB – University of Trieste 15 June 2005 - slide 2

The technology vision 2020 CASLAB – University of Trieste 15 June 2005 - slide 3

Moore’s law for molecular dynamics CASLAB – University of Trieste 15 June 2005 - slide 4

Algorithms vs Hardware Monte Carlo algorithms to simulate Ising model n David Landau, U. of Georgia • 1 E 10 • 1 E 9 • 1 E 8 • relative performance • 1 E 7 • 1000000 • 10000 • 100 • computer speed • 10 • 1970 CASLAB – University of Trieste • 1975 • 1980 • 1985 • 1990 • 1995 • 2000 15 June 2005 - slide 5

THE CHEMICAL SUPPLY CHAIN Chemical and Process Engineering is now concerned with the understanding and development of systematic procedures for the design and operation of chemical process systems, ranging FROM nano and microsystems-scales where chemicals have to be synthesize and characterize at the molecular-level TO industrial-scale continuous and batch processes Needs of modeling !!! CASLAB – University of Trieste 15 June 2005 - slide 6

Hierarchy of Scales Polymer morphology; blend phase separation; composite structure Critical constants; phase equilibria; PVT data; diffusivity, viscosity Molecular structure; free energies of formation, reaction; dipole moments and other spectroscopic properties; reaction rates CASLAB – University of Trieste 15 June 2005 - slide 7

Molecular Modeling: innovative approaches Mesoscale simulation n Dissipative Particle Dynamics – Mesoscopic Particle based model w Solve dynamical equations of motion for positions, velocities of beads in the Langevin dynamics and n Mesoscale Dynamics (Meso. Dyn) - Mesoscopic Field based model w Dynamic mean-field density functional theory coupled with Langevin equation of motion n Both require the definition of beads and bead interaction energies Flow and continuum mechanics models n Solve PDA and continuum models including hydrodynamic description and phenomena occurring at macroscopic level w Finite elements simulation w Starting from a grid definition n To be applied for nano-materials a detailed description of the properties at mesoscale level is needed CASLAB – University of Trieste 15 June 2005 - slide 8

Research Fields Process simulation: process synthesis, design, modeling Material Sciences: thermo physical properties for materials Life Sciences: drug-receptor interactions, drug-design, QSAR, drug-delivery… Data-base and Web Applications development CASLAB – University of Trieste 15 June 2005 - slide 9

Process simulation Developing new process flow-sheets or modifying existing ones … … to convert raw materials in new products: minimum cost maximum profit energy efficiency good operability with respect to n n n flexibility controllability reliability safety environmental regulations PROJECTS Optimization of continuous and batch processes; Simulation of essential oil extraction from medicinal plants; Energy optimization for refrigeration industry and thermodynamic modeling of new refrigerants; Process Simulation and Sustainable industrial development with algorithm for the estimation of potential impact environmental indexes Steady state and dynamic simulation of fuel cells and its integration with biomass gasification. CASLAB – University of Trieste 15 June 2005 - slide 10

Material Science Selection of consistent and reliable method for the calculation of thermo physical properties for fluids by means of Equation of state; development and application of theoretical computer simulation techniques for the study of thermodynamic properties of fluids, solids and materials at conditions inaccessible to experiment; fundamental understanding of the microscopic basis for observed macroscopic properties with particular attention to the nanoscale and nanosciences; predict thermodynamic properties that may be used as input into the engineering models for: n n n fluids solids polymers including nanoscale compounds. CASLAB – University of Trieste 15 June 2005 - slide 11

Material Science: methods Quantum chemistry techniques Molecular Dynamics and Molecular Mechanics Monte Carlo simulations Force Field development Quantum mechanics continuous solvation models QSAR and group contribution methods Equation of state and perturbation theory Meso-scale Modeling by Dissipative Particle Dynamics Meso-scale Modeling by Mesodyn CASLAB – University of Trieste 15 June 2005 - slide 12

Material science: current projects Title Project Objective Methods Nanocomposite PET-MMT as barrier materials SIPA To increase the barrier effect for diffusion of gases MD-MC Innovative molecular modeling approach to up-grade polymeric materials from post industrial rejects EU-STREP Mo. Mo Modeling of polymer blends and polymer nanocomposites Multi scale modeling NANOPACK: design and development of nanostructured materials for packaging PRIN 2005 Modeling of diffusion of gases and barrier effect in polymer (PET, PETPEN) film Multi scale modeling Development of ab-initio force fields for fluorocarbons IUPAC DFT calculation for development of FF and CSM (COSMO) QM-MM-MDCOSMO In silico prediction of medium effects on esterification equilibrium using the cosmo-rs method Dept. of Pharmaceutical Sciences UNITS and West. CHEM, Glasgow Prediction of solvent effect in industrial biocatalyzed reactions by QM calculations DFT-COSMO CASLAB – University of Trieste 15 June 2005 - slide 13

Examples: polymer science (1) Atomistic scale: parameters determination n Determination of parameters of semi empirical equations of state for polymer solutions: PHSCT and Lattice Fluid w Fermeglia M. , Pricl S. AICh. E J. 45: 2619 -2627 (1999) Atomistic scale: Effect of compatibilizer on the nanocomposite n Standard plastics: nylon 6 w Fermeglia M. , Ferrone M. , Pricl S. Fluid Phase Equilibria 212: 315 -329 (2003) n Standard plastics: PP and PP maleated + basal spacing w Toth R. , Coslanich A. , Ferrone M. , Fermeglia M. , Pricl S. , Miertus S. , Chiellini E. Polymer 45: 8075 -8083 (2004) n Bio. Degradable Plastics: butylene terephtalate-co-thiodiethylene terephtalate w Fermeglia M. , Ferrone M. , Pricl S. , Molecular Simulation 30: 289 -300 (2004) n Bio polymers: hydrotalcite – poly (g hydroxy butirate) and poly (vinyl alcohol) + non steroidal anti inflammatory drugs (NSAIDS) w Toth R. , Fermeglia M. , Ferrone M. , Miertus S. , Chiellini E. , Pricl S. , submitted Biomacromolecules n n Industrial cooperation: PET and barrier effect Recycled polymers: PMMA – alternative compatibilizer CASLAB – University of Trieste w EU STREP Mo. Mo Project 15 June 2005 - slide 14

Examples: polymer science (2) Mesoscale: blends n Industrial problem Solvay: LDPE – PVC w Fermeglia M, Coslanich A, Ferrone M, Pricl S, Paneni M. S. , Humar T, Paglione E. , AICh. E 2004 n PET - PEN compatibility and mechanism of blending w Fermeglia M. , Ferrone M. , Cosoli, P. , Piccarolo S. , Mensitieri G. , Pricl S. , AICh. E 2005 n ABS – PC: EU Mo. Mo Project Mesoscale: block copolymers n Diblock copolymers for the automotive industry: PMMA - PMBA - PCN w Coslanich A. , Fermeglia M. , Ferrone M. , Paneni M. S. , Pricl S. , Martinelli L. , Sinesi S. , In Computational Modeling and Simulation of Materials, (2004) Mesoscale and finite elements n LDPE – PP at different MW: mechanical properties of the material with multiscale approach CASLAB – University of Trieste 15 June 2005 - slide 15

Life science 1 Drug design and modeling: n n n HCV and HIV virus inhibitors; Candida spp. and Micobacterium tuberculosis spp. Inhibitors; Syncitial respiratory virus inhibitors; Prion proteins and neurodegenerative disorders etiological agents; RNA+ virus inhibitors… Structure/activity relationships for mutant proteins: n n n P 53 (MPNST; Ovarian Carcinoma; Li-Fraumeni Syndrome, …) Bcr-Abl (CML) c-kit (GIST) PDGFRA (hyper) human b-myosin (F-HCM)… CASLAB – University of Trieste 15 June 2005 - slide 16

Life science 2 Drug/receptor interactions: n n n Discovery of binding modes; Mechanisms and thermodynamics of binding; Enzymatic Activity inhibition prediction (e. g. IC 50); Effect of mutations on binding; Prediction of resistant mutants; Ad hoc drug modification and/or design… Design of drug delivery systems: n n Bioconjugate systems for targeting cancer cells. . Bio-dendrimers for delivery, protein-mimicking and implantation devices… Homology modeling of proteins QSAR investigations: n High-throughput drug design via 3 D pharmacophore modeling… CASLAB – University of Trieste 15 June 2005 - slide 17

Life science: current projects 1 Title Project Objective Methods Drug-discovery for HIV and HCV FIRB Development of anti- viral drugs for HIV and HCV MM – MD – QSAR - free energy calculations Thermodynamic and structural characterization of dendrimers Cooperation with Freie Universitat Berlin To obtain information for synthesis, properties and use of such molecules MD and MM “Identificatori di biomarcatori per la diagnosi precoce, il monitoraggio, la prevenzione o come bersaglio terapeutico nei tumori” Ricerca finalizzata – Istituto Nazionale per lo studio e la cura dei tumori di Milano Formulate a rationale for drug and/or therapy optimization MM – MD – QSAR - docking Supermolecular structures as carriers for poorly soluble drugs or targeted drug delivery Cooperation with University of Padua Find alternatives for control drug release MD – MM – Monte Carlo CASLAB – University of Trieste 15 June 2005 - slide 18

Life science: current projects 2 Title Project Objective Methods Pathogenetic pathways, determining pharmacological response: a novel tumoral functional classification approach AIRC 2004 – INSCTM Formulate a rationale for drug and/or therapy optimization MD-MM-Docking -free energy calculations Analysis of response mechanisms to imatinib in soft tissue sarcomas AIRC 2005 – INSCTM Obtain 3 D models of protein and formulate a rationale for drug and/or therapy optimization MD-MM-Docking -free energy calculations Protein mutation analysis in tumors INSCTM SAR for P 53, Bcr. Abl, c-kit, PDGFRA Free energy perturbation, MD, CASLAB – University of Trieste 15 June 2005 - slide 19

Examples: Life science (1) Drug design and modeling n Antimycobacterial activity of new 3 -substituted 5 -(pyridin-4 -yl)-3 H-1, 3, 4 oxadiazol-2 -one and 2 -thione derivatives. Preliminary molecular modelling investigations w Mamolo M. G. , Zampieri D. , Vio L. , Fermeglia M. , Ferrone M. , Pricl S. , Scialino G. , Banfi E. Bioorganic & Medicinal Chemistry 13: 3797 -3809 (2005) Structure/activity relationships for mutant proteins n TT 315 I mutated bcr-abl in chronic myeloid leukemia and imatinib: insights from a computational study w Fermeglia M. , Ferrone M. , Tamborini E. , Pricl S. Molecular Cancer Therapeutics, Proofs revised Drug/receptor interactions n Hindered nucleoside analogs as hinibitors of HCV RNA-dependent RNApolymerase: evolving vistas w Manfredini S. , Angusti A. , Ciliberti N. , Durini E. , Vertuani S. , Buzzoni L. , Coslanich A. , Fermeglia M. , Ferrone M. , Paneni M. S. , Pricl S. , La Colla P. , Sanna G. , Cadeddu A. , Mura M. , Loddo R "Framing the knowledge of viral hepatitis", edited by Rymond F. Schinasi, IHL Press, Arlington MA, US (2005) IN PRESS n Prediction fo HIV-1 resistance to NNRITs: a computer-aided molecularbased rationale w Pricl S. , Coslanich A. , Fermeglia M. , Ferrone M. , Paneni M. S. , Loddo R. , Cabizza A. , Sanna G. , Murreddu M. , La Colla P. HIV Dart 2004, Montego Bay, Jamaica 2004 1: 47 -48 (2004) WINNER OF POSTER AWARD CASLAB – University of Trieste 15 June 2005 - slide 20

Examples: Life science (2) Design of drug delivery systems n Synthesis and physico-chemical characterization of folatecyclodextrin bioconjugate for active drug delivery w Caliceti P. , Salmaso S. , Carofiglio T. , Fornasier R. , Fermeglia M. , Ferrone M. , Pricl S. Bioconjugate Chemistry 14: 899 -908 (2003) n Polyamidoamine (yet not PAMAM) Dendrimers as Bioinspired Materials for Drug Delivery: Structure-Activity Relationships by Molecular Simulations w Metullio L. , Ferrone M. , Coslanich A. , Fuchs S. , Fermeglia M. , Paneni M. S. , Pricl S. Biomacromolecules 5: 1371 -1378 (2004) Homology modeling of proteins n Structural and energetical analysis of ATP-binding pocket mutations of the cardiac beta-myosin heavy chain implicated in familial hypertrophic cardiomyopathy w Pricl S. , Fermeglia M. , Ferrone M. , Paneni M. S. , Carniel E. , Mestroni L. Circulation research, submitted 2005 CASLAB – University of Trieste 15 June 2005 - slide 21

Data-base and Web distribution Relational data-base structure and development in SQL environment; Data-base distribution in Internet and Data Access technology; Client server and multi tier software development; Web Services and XML; Portals. CASLAB – University of Trieste 15 June 2005 - slide 22

Computing facilities: HW User support: 4 Microsoft® Window 2003 Server® n n File Server (4 Terabyte storage) Data Base Server (1 Terabyte storage) Web Server Print Server Calculation local servers n n n 3 Microsoft® Window XP ® Intel Xeon bi processor (RAID) for intensive calculations 1 Microsoft® Window XP ® Intel Xeon graphic workstation for rendering SGI Origin R 10000 - Unix Iris 6. 4 Calculation server SGI Onyx R 10000 – Unix Iris 6. 5 Rendering and graphic WS 4 SGI Octane R 12000 – Unix 6. 5 calculation and graphic WS 1 SGI Octane R 12000 bi processor – Unix 6. 5 calculation and graphic WS Clients Windows XP LAN switched 100 - 1000 Mbs – Wireless Printers and facilities CASLAB – University of Trieste 15 June 2005 - slide 23

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Computing facilities: SW Process Simulation: Aspen. Tech Engineering suite n Steady state PS, Dynamic PS, Heat Exchanger design, Batch+, Pinch technology, Cost Estimation, Polymers+, Batch Distillation … Molecular Modeling Material science: Accelrys Cerius 2 n n n DMOL, Gaussian, … Visualizer, MD, Monte Carlo, Sorption, Synthia, Blend, … DPD, Mesodyne Molecular Modeling Material science: Material Studio 3. 2 n Visualizer, Builders, Discover, MD, MC, MEsoscale, Mesoprop Molecular Modeling Life Science: n n n Accelrys Insight II and Catalyst Amber VMD-Namd, Thinker, Gold, Surflex, Autodock, Chimera, Swiss-Pdb, Q, Modeller… In house developed programs n n n Thermo physical calculations by EOS Add on to commercial packages Mesoscale DDFT Support Software n SQL server Data Base Server, Developer tools, … CASLAB – University of Trieste 15 June 2005 - slide 25

Personeel 2 Staff n n Maurizio Fermeglia Sabrina Pricl 4 PHD students n n Marco Ferrone Maria Silvia Paneni Letitia Toma Alessandro Coslanich 2 research contracts n n Paolo Cosoli Luca Tomasi Variable number of master students (3 -5) CASLAB – University of Trieste 15 June 2005 - slide 26

For further information please contact Maurizio Fermeglia (Mauf@dicamp. units. it), DICAMP, University of Trieste Sabrina Pricl (Sabrinap@dicamp. units. it) DICAMP, University of Trieste