MOLECULAR MODELING AND SIMULATION
People
Riccardo Farchioni
Giuseppe Grosso
Giuseppe Maccari (CNI-iit)
Paolo Mereghetti (CNI-iit)
Riccardo Nifosí
Valentina Tozzini – v.tozzini@sns.it
Fabio Trovato
Contents:
Models and methods development
Applications to biomolecular systems
Applications to complex organic systems
The research at the NEST unit of the Nanoscience Institute includes a transversal activity of molecular modeling and simulation with applications spanning over the NanoPhysics and NanoBioScience research lines. The used methods include Quantum Chemistry (QM) calculations (mainly based on Density Functional Theory (DFT)), all-atom (AA) Force Field simulations, and the development of Coarse Grained (CG) and meso-scale models. The different models and methods are applied separately or combined in multi-scale approaches.
Models and methods development
In the latest years we have been involved in the development of CG models for biopolymers representing proteins and nucleic acids at the level of a single interacting center for each amino acid or nucleotide. Due to their simplicity these “minimalist” models allow to largely extend the size and time scale in molecular dynamics simulations. The accuracy and predictive power in such simple models can be preserved by an optimized parameterization. Our optimization strategy is to include as much knowledge coming from experiment as possible, in particularly using at best the huge amount of structural information from the PDB repository of experimental structures, and other macroscopic or thermodynamic information. We developed specific statistical analysis procedures and a Genetic Algorithm (GA) to combine this information within a coherent parameterization, which is being tested on RNA, DNA and polypeptides.
Following the idea of reducing at minimum the cost of simulations, and with a similar heuristic-based parameterization strategy including information from different sources, we developed a meso-scale model of the cytoplasm, representing the crowder molecules as spheres with different sizes and interacting potentials. This model, mimicking the cytoplasm of the bacterium Escherichia coli, is able to reproduce with high accuracy the diffusive behavior of the different species.
We are also working to incorporate these models into multi-scale approaches, combining the resolutions from the atomistic one (including also the QM level in some cases) up to the meso-scale. The multi-scale approach, extremely useful for biomolecular systems, is currently under consideration also for non-biological systems.
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Fig 1: (a) Resolution levels in the multi-scale approach represented using the Green Fluorescent Protein (GFP). From left to right: QM approach (mainly using Density Functional Theory), the atomistic representation with empirical Force Fields (Amber, Charmm, Gromos, and OPLS), Coarse Grained (with our developed minimalist model), mesoscale representation (single domains represented as spheres), and the cytoplasm representation combined with CG representation of the GFP. The main tasks addressed for each level are reported. (b) Multi-scale and multi-methodological approach to biopolymer study: Exp information (structure or other data) are combined with secondary structure prediction algorithms and complemented by atomistic simulation by means of heuristic algorithms (GA) to parameterize an accurate and predictive CG model for proteins or nucleic acids.
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A meso-scale model for the Cytoplasm of Escherichia Coli
Fabio Trovato, Valentina Tozzini,
in preparation
Selection and statistical analysis of secondary structures in Proteins Data Bases
G Spampinato, G Maccari, V Tozzini,
in preparation
A multi-scale and multi-stable model for the photocyle of rhodopsins
F Tavanti, V Tozzini,
in preparation
Minimalist Models for Biopolymers: Open Problems, Latest Advances and Perspectives
Fabio Trovato, Valentina Tozzini,
AIP Conf. Proc. 1456 187-200 (2012)
Genetic Algorithm Optimization of Force Field Parameters. Application to a Coarse-Grained Model of RNA
F Leonarski, F Trovato, V Tozzini, J Trylska,
Proceeding EvoBIO’11 – Lecture Notes in Computer Science, Springer, 6623 147-152 (2011)
RNA dynamics with one-bead coarse-grained model
Leonarski, F Trovato, V Tozzini, and J Trylska,
Abstract of the Papers of the American Chemical Society 241, 285-COMP (2011)
Minimalist models for proteins: a comparative analysis
Valentina Tozzini,
Quart Rev Biophys, 43, 333-371 (2010)
Multiscale Modeling of Proteins
Valentina Tozzini,
Accounts Chem Res 43, 220 (2010)
Applications to biomolecular systems
We applied the multi-scale approaches to a number of different systems. In the Green Fluorescen Proteins family, with a DFT approach we studied the optical properties and correlated them with structural/vibrational ones. We complemented the QM studies with AA simulations in order to identify the molecular mechanisms of GFP photoswitching and to investigate the chromophore-formation mechanism. We used QM/MM hybrid approach to understand the spectral tuning in GFP and its red variants. We simulated the GFP diffusional and aggregation behavior using its CG model within the mesoscale cytoplasm model. These results can be directly compared with FRAP and FRET experiments.
These models were exported to different systems. One- and two-photon excitation properties were studied through DFT response theory on coumarine derivatives and on structures inspired by the GFP chromophore, to aid the rational design of novel solvatochromic probes for intracellular measurements.
The action mechanism of proteins involved in the HIV replications was studied by means of CG models. In particular the binding of HIV-1 protease to the Gag viral poly-protein is currently in the course. Other systems under examination are the self-aggregating β-2 microglobulin (involved in the dialyzed patients arthritis) and the unstructured α-syn nuclein (involved in the Parkinson disease). In all cases the goal of the study is to understand the molecular mechanisms underlying the pathological process in order to interfere with it.
Another field of application is the targeted drug delivery, i.e. the capability of targeting drugs or other biologically active entities to specific tissues/cells within an organism, thus minimizing side effects from a systemic treatment.
Our activity targets the structure prediction and sequence optimization of three systems devised for delivery. These are: cell-penetrating peptides, DNA aptamers, and gold nanoparticles coated with a suitably functionalized small peptide. All the target systems lack a precise structural characterization and a mechanistic description of their activity.
In the case of the cell penetrating peptide the starting point is a hybrid 30 amino acid sequence of Tat11 (a well known cell penetrating peptide, internalized through endocitosis) and of CM18 (an antimicrobial peptide), the structure of which has been investigated by CD spectroscopy and molecular dynamics simulations. A detailed understanding of the interactions of this peptide with the membrane will suggest new sequences with improved properties, also considering the possibility to include in the sequence non-natural amino acids. The optimization of peptide sequence is also addressed through bioinformatic approaches.
A DNA-protein complex is instead involved in the cellular internalization of the aptamer GS24, a sequence of 50 nucleotides, which binds to the extracellular domain of the transferrin receptor. Since the aptamer structure is unknown, multi-scale simulations are used to perform folding and to test the stability of the various possible secondary structures. The predicted 3D structure of GS24 will be used for building a model for the GS24-transferrin receptor complex.
The third system involves shorter peptide sequences bound via the thiol bond to the surface of a gold nanoparticle
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Fig 2: a) all-atom simulations of the interaction between a peptide and a lipid bilayer b) secondary structure model of the GS24 aptamer and cartoon molden transferring receptor’s X-ray structure c) Au Nanoparticle based system for photocontrolled delivery of payloads to the cell, via a photocleavable triazole moiety. Both the system scheme (right) of and an all-atom rendering (left) are shown.
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Spectral “Fine” Tuning in Fluorescent Proteins: The Case of the GFP-Like Chromophore in the Anionic Protonation State
P Amat and R Nifosì,
J. Chem. Theory Comput., , 9 : 497–508 (2013)
Diffusion and aggregation properties of FPs within the cytoplasm: a coarse-grained - mesoscale model
F Trovato, R Nifosì,
in preparation
A Coarse Grained Model for the dynamics of binding of the HIV-1 protease to Gag
M Galimberti, V Tozzini,
in preparation
Multi-scale dynamics of β-2 microglobulin: the fibrillogenic intermediate
A Bochicchio, O Carrillo, G Brancolini, S Corni, V Tozzini,
in preparation
From sequence to function: a study on DNA aptamer interaction with transferrin receptor
D Porciani, G Signore, L Marchetti, R Nifosì, P Mereghetti, F Beltram,
in preparation
A novel chimeric cell-penetrating peptide with membrane-disruptive properties for efficient endosomal escape
Salomone F, Cardarelli F, Di Luca M, Boccardi C, Nifosì R, Bardi G, Di Bari L, Serresi M, Beltram F,
J Control Release. 163:293-303. doi: 10.1016/j.jconrel.2012.09.019 (2012)
Multiphoton molecular photorelease in click-chemistry-functionalized gold nanoparticles
Voliani V, Ricci F, Signore G, Nifosì R, Luin S, Beltram F,
Small (2011)
Vibrational spectroscopy of fluorescent proteins: a tool to investigate the structure of the chromophore and its environment
V Tozzini and S Luin,
in Springer Series on Fluorescence, 113, (2011)
One- and two-photon excitation of fluorescent proteins
R Nifosì and V Tozzini,
Springer Series on Fluorescence, 113, (2011)
Photoswitching of E222Q GFP mutants: "concerted" mechanism of chromophore isomerization and protonation
S. Abbruzzetti, R. Bizzarri, S. Luin, R. Nifosì, B. Storti, C. Viappiani, F. Beltram,
Photochem & Photobiol Sci, 9, 1307-1319 (2010)
A role for molecular compression in the post-translational formation of the Green Fluorescent Protein chromophore
U Terranova, R Nifosì,
Chem Phys, 371, 76-83 (2010)
GCN5-dependent acetylation of HIV-1 integrase enhances viral integration
M. Terreni, P. Valentini, V. Liverani, M.I. Gutierrez, C. Di Primio, A. Di Fenza, V. Tozzini, A. Allouch, A. Albanese, M. Giacca, and M. Cereseto,
Retrovirology 7, 18 (2010)
Polarity-Sensitive Coumarins Tailored to Live Cell Imaging
G. Signore, R. Nifosì, L. Albertazzi, B. Storti and R. Bizzarri,
J Am Chem Soc, 132, 1276–1288 (2010)
Raman study of chromophore states in photochromic Intrinsically Fluorescent Proteins
S Luin, V Voliani, G Lanza, R Bizzarri, R Nifosì, P Amat, V Tozzini, M Serresi, F Beltram,
Am Chem Soc, 131, 96-203 (2009)
A novel coumarin fluorescent sensor to probe polarity around biomolecules
G. Signore, R. Nifosì R, L. Albertazzi, R. Bizzarri,
J Biomed Nanotechnol. 5, 722-9 (2009)
Applications to complex organic systems
DFT based calculations and simulations are also used to study the properties of graphene systems with controlled hydrogenation. Nanoribbons of graphene sculpted in a fully hydrogenated matrix (called graphane) display semiconductor properties depending on their width. In addition, Car-Parrinello simulations show that controlled graphene hydrogenation could be obtained by corrugating graphene, which induces atomic hydrogen spontaneous chemisorption on the convex regions and desorption by curvature inversion. These mechanisms are under consideration for two practical applications: one is the possibility of using graphene based systems for a hydrogen storage device based on graphene, in which loading and release of H is controlled by the curvature manipulation. The second is the possibility of building nano-electronic devices with tailored properties by controlling the topology of the hydrogenated-dehydrogenated areas by means of the curvature. These possibilities are currently being explored combining DFT calculations and simulations based on empirical force fields, needed to address the multiple nm scale, with information coming from experiment.
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Fig 3: Modeling graphene based systems. (a) Electronic properties of graphene-graphane hybrid systems. Gap value dependence on width in the graphene nanoribbon in graphane. (b) Corrugated graphene sheet by lateral compression, variation of binding energy vs curvature (red=convex, bla=flat, blue=concave); hydrogen loaded on convex sites.
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DFT based calculations are also adopted for the study of structural, electronic and optical properties of conjugated polymers, which are used in blends with fullerene derivatives for solar cells. [C60]-PCBM is actually the most used and well performing organic semiconductor electron acceptor, in particular when blended with the electron donor Poly(3-hexylthiophene) (P3HT). Despite this, the morphology of these systems at the nanoscale, a key point for their efficiency, is not well understood. Thus, this is just the main task of our theoretical and numerical investigation, which are based on DFT for structural optimization, Car-Parrinello molecular dynamics and the nudged elastic band method to follow the geometrical evolution of the structure, plane waves and Gaussians for the electronic and optical properties, and the Keldysh Green’s function method for the transport properties of the optimized structures.
The general adopted strategy starts from structural experiments and arrives to one-electron model Hamiltonians for the selected organic crystals or polymers; it can be summarized in the following steps:
- Quantitative interpretation of the experimental XRD spectra exploiting global optimization algorithms to solve the structure by trials in direct space. This procedure is complemented by ab-initio minimization of the total energy per cell in order to determine the arrangement of the atoms in the cell.
- From the above information the electronic structure of the system is evaluated by first-principle DFT methods including van der Waals interactions. Optical properties including collective effects are evaluated exploiting GW and Bethe-Salpeter equation.
- Construction of effective chain-like Hamiltonians mapping the original ab-initio Hamiltonian, to be used for the calculation of the charge transport properties of the biased molecular devices
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Fig 4: (a)XRD pattern of crystalline PCBM. (b) Monoclinic primitive cell obtained by modeling. (c) Corresponding PCBM molecular packing view along b-axis (d) Packing of cells of the crystalline P3HT polymer
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The influence of graphene curvature on hydrogen adsorption: towards hydrogen storage devices
S Goler, C Coletti, V Tozzini, V Piazza, T Mashoff, F Beltram, V Pellegrini, S Heun,
submitted
Multi-scale simulations of hydrogenated graphene systems
R Farchioni, V Tozzini,
in preparation
Prospects for Hydrogen Storage in Graphene
V Tozzini, V Pellegrini,
Phys Chem Chem Phys, 15 80-89 (2013)
Electronic trasmission through a polyacene ladder with a substitutional edge impurity
M Bravi, R Farchioni, G Grosso, and G Pastori Parravicini ,
Phys. Rev. B 87, 035105- 035114 (2013)
Quenching of the transmittivity of a one-dimensional binary random dimer model through side-attached atoms
R Farchioni, G Grosso and G Pastori Parravicini ,
Phys. Rev. B 85, 165115-165121 (2012)
Anisotropic molecular packing of soluble C60 fullerenes in hexagonal nanocrystals obtained by solvent vapour annealing
R Colle, G Grosso, A Ronzani, M Gazzano, V Palermo,
Carbon 50, 1332-1337 (2012)
Electronic transmission through a ladder with a single side attached impurity
R Farchioni, G Grosso and G Pastori Parravicini,
Eur. Phys. J. B 84, 227-233 (2011)
Structure and X-ray spectrum of crystalline poly(3-hexylthiophene) from DFT-van der Waals calculations
R. Colle, G. Grosso, A. Ronzani, and C. M. Zicovich-Wilson,
Phys. Status Solidi B, Phys. Status Solidi B 248, 1360-1368 (2011)
Reversible Hydrogen Storage by Controlled Buckling of Graphene Layers
V Tozzini, V Pellegrini,
J Phys Chem C, 115 25523-25528 (2011)
Electronic structure and Peierls instability in graphene nanoribbons sculpted in graphane
V. Tozzini and V. Pellegrini,
Phys Rev B 81, 113404 (2010)
Acidification of three-dimensional Emeraldine polymers: search for minimum energy paths from base to salt
C. Cavazzoni, R. Colle, R. Farchioni and G. Grosso,
J. Chem. Phys. 128, 234903-234907 (2008)