The Laboratoire d’Ingénierie des Fonctions Moléculaires was officially opened in September 2010 after his head, Marco Cecchini, was appointed junior director at ISIS. The peculiarity of the Lab is to sit right at the interface between the domains of life science and material science with supramolecular chemistry making the bridge between them. Our working approach is to start from “real” problems of medical or technological relevance and develop computational strategies to provide an orthogonal and hopefully insightful view to problems. It follows that methodological development lies at the very heart of the Lab where different competences and skills converge to develop models that capture the fundamental nature of phenomena.
Fundamental problems concerning the elucidation of the design principles for molecular self-assembly, the allosteric regulation of important receptors mediating synaptic transmission, and the development of efficient strategies to compute the free energy of conformation in solution are being tackled.
- Predicting molecular self-assembly at surfaces and interfaces
Molecular self-assembly is one of the most significant phenomena at the nanoscale, which provides the path of lowest energy consumption to the fabrication of nano-objects with controlled morphologies and properties. Among its multiple facets, molecular self-assembly at surfaces and interfaces stands out as a prominent example with tremendous technological applications. We aim at developing a novel theoretical approach based on the combination of atomistic modeling and statistical mechanics for a first-principle interpretation of the thermodynamic stability of the SAM. Earlier version of this theory proved useful for rationalizing the chain-length dependence of the graphite-exfoliation yield in the presence of fatty acids and providing an interpretation of the competitive equilibrium of three diarylethene derivatives self-assembly on graphite. Our ultimate goal is to devise a self-consistent framework for the assessment of the thermodynamic stability of the SAM, the interpretation of the concentration dependence of 2D self-assembly, and the rationalization of competitive self-assembly equilibria at surfaces and interfaces.
- Allosteric regulation of ligand-gated ion channels
Pentameric ligand-gated ion channels (pLGICs) play a central role in the intercellular communication in the nervous system and are involved in fundamental processes such as learning, attention, and memory. They are oligomeric protein assemblies that convert a chemical signal, typically a local increase in the extracellular concentration of
neurotransmitter, into an ion flux through the postsynaptic membrane, which mediates the transmission of an action potential across a synapse. Despite pLGICs have attracted significant interest for more than 150 years, the molecular mechanism of signal transduction remains to be elucidated. Starting with structural information at high resolution, we aim at providing a mechanistic description of ion gating in pLGICs and their allosteric modulation by Molecular Dynamics simulations. Elucidating the link between the functional isomerization of the receptor and the structural changes at the ligand-binding sites is the ultimate goal of our analysis.
- Calculation of the free energy of conformation
Bio-molecular machines such as enzymes, motors and switches perform a wide range of essential functions in the cell by cycling through a series of distinct conformational states. In solution these states are in equilibrium and the probability of finding the biomolecule in a given conformation is related to its free energy. Providing means to determine the free energy of conformation from first principles, i.e. using high-resolution structures and physics-based models, will open to a quantitative understanding of protein function and regulation. We have recently developed an elegant approach for the accurate determination of the free energy of conformation with an explicit treatment of the solvent. The confinement/solvation free energy (CSF) approach aims at the free energy of molecular conformers in solution by transforming them into harmonic states in vacuum, whose absolute free energy is exact. Our current goal is to extend the methodology to protein-ligand binding and use it to explore solvation effects in 2D self-assembly.