RNA modeling

For a long time the importance of ribonucleic acid (RNA) in molecular biology has been obfuscated by its famous cousin, DNA, and by proteins. However, in the last decade, a number of biological functions accomplished by RNA have been discovered, the most famous one probably being RNA interference, which lead to the Nobel Prize in Medicine in 2006.A peculiar characteristic which distinguishes RNA from DNA is that, while the latter has a more or less regular double-helix structure, the former is single stranded and can fold in different manners depending on its specific sequence of nucleotides. In this sense, RNA is similar to proteins, where the three-dimensional structure is dictated in a non-trivial manner by the sequence of aminoacids. This raises the issue of RNA folding, i.e. the prediction of the three-dimensional structure of a RNA molecule given its nucleotide sequence, which can be of great help in the interpretation of a variety of experimental studies on small RNA molecules.

As a source of additional complexity, RNA is never working alone in the cell, and it is in constant interaction with other molecules (proteins) and with external conditions which can drive RNA out of equilibrium. Whereas nonequilibrium conditions are common in in vivo molecular biology, they are often neglected in in vitro experiments. A notable exception are single-molecule experiments, such as those where a single biopolymer is mechanically stretched out of its equilibrium condition. The recent advances in these experimental techniques call for an extra effort in their computational counterpart, which could provide insight on the role of important factors such as solvent molecules and/or counterions in RNA folding and behavior.

Our research activity is oriented towards the development of new computational tools for RNA modeling, and their application to the problems mentioned above. Our toolkit includes molecular dynamics simulations at the atomistic scale, coarse-grained models, and state-of-the-art methods for rare-event sampling.

For more details on the methodologies, click here.

Mechanism for RNA unwinding

F. Colizzi and G. Bussi

RNA unwinding from reweighted pulling simulations

J. Am. Chem. Soc. 134, 5173 (2012)

Preprint: arXiv:1203.5866

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In this paper we discuss the mechanism for RNA unwinding using atomistic, explicit solvent, steered molecular dynamics in combination with a novel analysis method. The introduced analysis methods allows reconstructing the free-energy landscape with respect to a variable different from the pulled one. Our results are supported by many experimental findings (crystal-structure analysis, thermodynamics data and ultrafast spectroscopy), and indicate that there is an intrinsic asymmetry in the two strands of a RNA. In particular, we speculate that the directionality of some helicases might be due to this intrinsic property of the RNA double helix. Check also our JACS Image Challenge.

A method for RNA/peptide binding

T. N. Do, P. Carloni, G. Varani, and G. Bussi

RNA/peptide binding driven by electrostatics - Insight from bi-directional pulling simulations

J. Chem. Theory Comput, ASAP (2013)

In this paper we introduce a novel collective variable which can be used, in combination with steered molecular dynamics or metadynamics, to accelerate binding events driven by electrostatic interactions. We also introduce a reweighting scheme which can be used to simplify the analysis of bi-directional pullings. Our protocol is applied to characterize the binding of TAR (a RNA from HIV) and a cyclic peptide of pharmaceutical relevance, and allow us to reproduce correctly the experimental binding pose. The method will be available in a future release of plumed.

Unraveling the folding mechanism of the adenine riboswitch

F. Di Palma, F. Colizzi, and G. Bussi,

Ligand-induced stabilization of the aptamer terminal helix in the add adenine riboswitch

RNA 19, 1517 (2013)

In these paper we study the effect of the ligand on the add adenine riboswitch.

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