Understanding the structure-function relationships of nucleic acid systems using computational modelling
Understand the mechanism of RNA devicesThe functional roles exhibited by regulatory ribonucleic acids (RNAs) in natural systems and the relative simple construction of RNA molecules (using only the four diverse nucleotides) make this class of molecules a perfect candidate for the developing of synthetic RNA devices, able to control functional responses in cells. Riboswitches are natural aptamers that mainly occur within the untranslated region of messenger RNA. These natural RNA molecules regulate gene expression after binding with small ligands. Understanding the role of the molecular interactions in the binding of these systems, will help to define criteria for the design of new devices with the desired functions (e.i regulating genes activation/deactivation). Atomistic simulations together with free energy calculations will be used to address the problem (e.i. the role of specific component on the stability of the system will be investigated). The final aim will be to locate the key interactions for the switching mechanism.
Riboswitches: Molecule of the Month - October 2010
Riboswitches: A Common RNA Regulatory Element - 2010 Nature Education
Coarse-graining nucleic acidsMany biological relevant processes are intrinsically multiscale. For example, the ribonucleic acid packing evolves on mesoscopic length and time scale, but is also coupled to local, atomistic dynamics (e.g. residue fluctuation). Consequently, we need a computational approach able to connect the disparate spatial and temporal scale relevant to the cellular process into a single and unified methodology. Atomically detailed models are a powerful tool for investigating structure and dynamics over nanosecond time and nanometer length scales, while low-resolution coarse-grained models provide the capability for investigating the formation of larger-scale structure. The project aim to design a transferable and unbiased coarse grained model based on an underlying atomistic description together with a scale-bridging approach that allows to switch the level of resolution from coarse-grained and the atomistic scale during the simulation.
DNA and strand invasionThe identification of genes that play a key role in the development of a specific disease calls for the need of sequence-specific ligand that can act on DNA and induce gene silencing. From one side, there are scarce high-resolution structural information on these systems, on the other side there is an high biomedical interesting to information on the structure and stabilization of these complexes. Atomistic simulation is a valid alternative to more expensive standard experimental technique to acquire structural and thermodynamic information on DNA binding system.
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Relevant publicationsA. Villa, C. Peter, and N. F. A. van der Vegt.
Transferability of non-bonded interaction potentials for coarse-grained simulations: Benzene in water,
J. Chem. Theory Comput. 2010, 6, 2434-2444.
A. Villa, C. Peter, and N. F. A. van der Vegt.
Self-assembling dipeptides: conformational sampling in solvent-free coarse-grained simulation,
Phys. Chem. Chem. Phys. 2009, 11, 2068-2076.
A. Villa, N. F. A. van der Vegt, and C. Peter.
Self-assembling dipeptides: including solvent degrees of freedom in a coarse-grained model.
Phys. Chem. Chem. Phys. 2009, 11, 2077-2086.
A. Villa, J. Wöhnert, and Gerhard Stock.
Molecular dynamics simulation study of the binding of purine bases to the aptamer domain of the guanine sensing riboswitch,
Nucleic Acids Research 2009, 37, 4774-4786.
A. Villa, E. Widjajakusuma, and G. Stock
Molecular Dynamics Simulation of the Structure, Dynamics, and Thermostability of the RNA Hairpins uCACGg and cUUCGg
J. Phys. Chem. B 2008, 112, 134-142
J Ferner, A. Villa, E. Duchardt, E. Widjajakusuma, J. Wöhnert, G. Stock, and H. Schwalbe
NMR and MD studies of the temperature-dependent dynamics of RNA YNMG-tetraloops
Nucleic Acids Research 2008, 36, 1928-1940
A. Villa and G. Stock
What NMR Relaxation Can Tell Us about the Internal Motion of an RNA Hairpin: A Molecular Dynamics Simulation Study.
J. Chem. Theory Comput. 2006, 2, 1228 - 1236.