STRUCTURAL BIOINFORMATICS OF NORMAL AND PATHOLOGICAL MOLECULES
Team leader R. Charbel Maroun, PhD, HDR
Structural bioinformatics methodologies such as molecular modeling and simulation are applied to generate accurate three-dimensional models of biomolecules and their collective motions, leading to the prediction and study of physico-chemical and biological properties that are difficult to access by physical means. Molecular modeling allows the generation of 3D models and molecular dynamics simulations allow the exploration of the conformations and internal movements of the molecules. These methods are also useful to interpret experimental structural data or other source of information related to the atomic structure of biomolecules. The results of structural bioinformatics provide relevant information for fundamental science and the basic mechanisms of (bio)molecular function.
The understanding of the dynamics of microtubules and the role of the protein partners that regulate the cytoskeleton remains incomplete. In this laboratory, our work is aimed at enlightening fundamental processes of critical importance in biology, such as cell cycle and neurodegeneration. For this purpose, the structural bioinformatics group applies and develops methods for the study of the normal and pathological variants of proteins of the microtubule skeleton. The understanding of the difference between both behaviors should lead us to the molecular basis of disease.
- Molecular basis of pathogenic mutations
Molecular modeling and dynamics of proteins of the microtubule skeleton: spastin in interaction with its partners
Spastin (Spastic ParapleGia 4, SPG4) is a ubiquitous protein involved in several microtubule-dependent functions such as intracellular membrane traffic, cytokinesis and endoplasmic reticulum morphogenesis. Mutations of SPG4 induce hereditary Human Spastic Paraplegias (HSP) -genetic disorders characterized by progressive lower limb spasticity and weakness. At the cellular level this disease is characterized by a degeneration of cortico-spinal tract axons. To date, only symptomatic treatments partially improving spasticity are available for HSP patients -no preventive or curative treatments exist; thus, the importance of understanding the molecular mechanisms regulated by spastin underlying axon maintenance and function. In our laboratory an interdisciplinary approach (NMR, cell and molecular biology, optical and video microscopy, structural bioinformatics) is used for studying the physiological and pathological role of spastin and its regulation by molecular partners, several of which have been recently identified by us.
The goal of this research project is to analyze, via structural bioinformatics, the 3D structure and dynamics of spastin and its different domains, as well as the biomolecular interactions between these domains and known and unknown promising molecular partners. This knowledge should help us understand the mechanism of action of spastin and its pathogenic mutants, leading eventually to HSP-directed therapy.
Molecular basis of genetic disorders
In the context of collaboration with medical geneticists from Qatar, we provide, in complement to genetic data showing the association of monogenic mutations to pathological phenotypes, molecular information on the mechanisms behind that may link the observed mutation and the phenotype. Structural bioinformatics in this context accelerates understanding of the pathology, notably when no direct structural data are available.
- Molecular basis of signal transduction
GPCRs and the mechanism of signal transduction
In this project we study the structural and dynamical features of a histamine receptor with microsecond-scale all-atom molecular dynamics (MD) simulations as a way to understand better the mechanisms of signal transduction, inactivation and constitutive activity. For this purpose, we embed the receptor in a lipid bilayer membrane surrounded of water and salt ions. Three systems containing (i) the receptor coupled to the endogenous agonist, (ii) the receptor coupled to a specific and powerful inverse agonist, and (iii) the uncoupled receptor were prepared. The results of a detailed multi-level comparative analysis of the trajectories will allow us to propose molecular mechanisms for the different states of the receptor, as well as describe conformational changes taking place.
- Protein-protein interactions
Integral membrane proteins
Prediction of multimeric complexes of integral cell membrane proteins by computational approaches with the goal of understanding their modulation of cell signaling.
Biology, Physics, Biochemistry, Computer science, Chemistry, Mathematics
Structural bioinformatics, Model building, Molecular modeling and simulation
INSTRUCTOR 2005- present. UAM, Dept. of Biotechnology; Universidad Autonoma del Estado de Morelos, Centro de Biotecnologia; Escuela Superior de Medicina y Homéopatia, Instituto Politécnico Nacional, “Molecular Structural Bioinformatics: Theoretical and computational methods for the study of biological macromolecules”.
INSTRUCTOR 2004 UAM’s 30th anniversary. Mexico City, Mexico. Course in Molecular Structural Bioinformatics “Theoretical and computational methods for the study of biological macromolecules”.
LECTURER 2004. International School on Computational Sciences for Complex Systems in Biology (CSSB 2004). Rovereto, Italy. « Theoretical methods for the study of the 3D structure, the function and the recognition mechanisms of biological macromolecules ».
INSTRUCTOR 2004 EMBO course « Biomolecular Simulation », Institut Pasteur, Paris, France.
INSTRUCTOR 2003-2009. Departamento de Biotecnologia, Universidad Autonoma Metropolitana (UAM), Mexico, and Centro de Biotecnologia, Universidad Autonoma del Estado de Morelos (UAEM), Cuernavaca, Mexico. « Molecular structural bioinformatics: Theoretical and computational methods for the study of biological macromolecules ».
LECTURER 1999-2004. Institut Pasteur. DEA de Structure, Fonction et Ingénierie des Protéines, U. De Paris VII.
LECTURER 1990 – 1993. Université de Paris V, Faculté de Pharmacie. Master (DEA) of molecular pharmacochemistry, experimental pharmacology and metabolism.
LECTURER 1984 – 1986. Rutgers University, Chemistry Department.
TEACHING ASSISTANT 1977 – 1981. Louisiana State University, Chemistry Department.