A tutorial on theoretical methods for the functional analysis of inorganic complexes and metalloenzymes

Enzymes are fascinating biological machines that have evolved to catalyze chemical reactions in a highly efficient and selective manner. Energy transduction in living organisms rely on respiration or photosynthesis, whereby the free energy of redox reactions catalysed at the inorganic active site of redox enzymes is used to transfer electrons and protons over length scales ranging from Angstroms to micrometers. Many questions remain unanswered regarding the catalytic mechanism at the active site of theses redox enzymes, long range proton and electron transport, and the transport of small molecules from the solvent to the enzyme active site. This series of short lectures will introduce the use of theoretical methods for studying the molecular mechanism of such bioinorganic catalysts.

The workshop is organized at IMéRA (Institute for Advanced Study of Aix-Marseille University) as part of the residence of the scientific team that includes Jochen Blumberger, Luca de Gioia, Claudio Greco and Philippe Schollhammer.

Program:

9h. Luca De Gioia: « DFT calculations of bioinorganic compounds and catalysts »

10h. Claudio Greco: « QM/MM calculations of energy profile of biological reaction mechanisms. »

11h. Jochen Blumberger: « Molecular Dynamics calculations of electron, proton and ligand transport in proteins. »

12h. Lunch

13h30. Nicolas Ferré: "Bioluminescence of marine organisms investigated by QM/MM calculations."

14h30 Iñaki Tuñon: "Calculation of rate constants of enzymatic reactions using QM/MM MD Simulations"


Outlines of the lectures (45 min each):

9h. Luca De Gioia
Department of Biotechnology and Biosciences, University of Milan-Bicocca 
« DFT calculations of bioinorganic compounds and catalysts »
The role of computational chemistry in the design and characterization of biomimetic catalysts will be the focus of the lecture, with a specific emphasis on the discussion of models inspired by the structure of the active site of hydrogenases. In particular, I will briefly illustrate some conceptual and practical issues commonly encountered when using quantum chemical methods in the investigation of bioinorganic compounds.

10h. Claudio Greco

Department of Environmental and Earth Sciences, University of Milan-Bicocca
« QM/MM calculations of energy profile of biological reaction mechanisms. »
In my lecture, I will discuss the relevance of hybrid quantum mechanical/molecular mechanical (QM/MM) calculations within the field of theoretical enzymology. Focus will be put on the possibility of studying the structural properties of the active sites of metalloenzymes. By means of selected examples taken form recent literature, I will also provide an overview on the accuracy of modern QM/MM approaches in evaluating the energy profile of biological reaction mechanisms.

11h. Jochen Blumberger

University College London; Department of Physics and Astronomy,
« Molecular Dynamics calculations of electron, proton and ligand transport in proteins. »
In my tutorial talk I will give an introduction to state-of-the-art computational methods that together with experiment have the potential to unravel the mechanism, thermodynamics and kinetics for electron, proton and ligand transport in biological molecules. In particular, I will focus on molecular dynamics simulation, and how one can exploit this method to obtain properties that can be related to experimental measurements. Applications to a number of proteins will be discussed such as electron conducting bacterial nanowires (multiheme proteins), H2 producing and oxidizing enzymes (hydrogenases) and CO2 reducing enzymes (dehydrogenases).

12h. Lunch

13h30 Nicolas Ferré

Aix Marseille Université
"Bioluminescence of marine organisms investigated by QM/MM calculations."
Chemiluminescence, ie the transformation of chemical energy into light, can be very efficiently catalyzed by  enzymes called luciferases. The resulting bioluminescence is commonly used for various analysis, eg ... In my talk, I wll introduce the current state-of-the-art theoretical chemistry tools for modeling bioluminescence of marine organisms (Aequorea Victoria jellyfish, Obelia Longissima hydrozoan) which luciferases (aequorin, obelin) feature the coelenteramide light emitter. The main experimental hypothesis regarding the nature of the light emitters, ie the ion-pair between the coelenteramide phenolate and the protonated His22 residue, is not supported by our calculations.

14h30 Iñaki Tuñon

Université de Valence, Spain.
« Calculation of rate constants of enzymatic reactions using QM/MM MD Simulations »
Transition State Theory is the most popular theory to calculate the rate constant associated to chemical reactions. In this talk we will discuss about the practical application of TST to enzymatic reactions. In particular we will analyze the selection of an adequate reaction coordinate and the calculation of the associated free energy profile. We will show how to overcome some of the limitations of TST calculating the transmission coefficient and tunneling contribution. We will finish presenting the current debate in the field about participation of protein motions in the chemical step.