The focus of this research project will be on halogen bonding, namely any noncovalent interactions involving halogen atoms as electrophilic species (electron density acceptor sites, Lewis acids, halogen bonding-donors). In particular, the overall goal of the project will be to fully elucidate the capabilities and properties of halogen atoms as recognition sticky sites in the context of biomolecules. The general objective of this research project will be achieved through the application of a multi-dimensional approach to the understanding of the intermolecular interactions involving halogenated molecules in chemistry and biology.
The programme of work will centre around three closely integrated and synergistic strands.
The common theme is to exploit halogen bonding for the design of smart peptides and foldamers (Strand 1), the obtainment of complexes of polyhalogenated organic pollutants with serum proteins (Strand 2), and to assemble biomimetic sensors for polyhalogenated organic pollutants (Strand 3).
For the first time a multidisciplinary team composed by synthetic chemists, small molecule crystallographers, biologists, physicists, and protein crystallographers will join forces around the fundamental issues of:
a) Contributing to the establishment of the nature and properties of halogen bonding in ligand/biomolecule systems;
b) Improving our understanding of long-distance intermolecular interactions and their role on the energy profiles of biochemical transformations;
c) Facilitating preparation of more rationally designed new halogenated drugs;
d) Allowing for the mechanistic understanding of reactivity of halogen-containing molecules for the development of efficient and "green" synthetic and bioremediation methods.
The overall aim of this project is, therefore, to enlighten to the scientific community the potential that halogen bonding has to become a very powerful tool in the manipulation of molecular recognition phenomena in chemistry and biology.
The overall goal of the FOLDHALO project will be to fully elucidate the capabilities and properties of halogen atoms as recognition "sticky" sites in the context of biomolecules. The programme of work will centre around three closely integrated and synergistic strands.
The common theme is to exploit halogen bonding for the design of "smart" peptides and foldamers (Strand 1), the obtainment of complexes of polyhalogenated organic pollutants with serum proteins and antibodies (Strand 2), and to assemble biomimetic sensors for polyhalogenated organic pollutants (Strand 3).
The overall aim of this project is, therefore, to enlighten to the scientific community the potential that halogen bonding has to become a very powerful tool in the manipulation of molecular recognition phenomena in chemistry, biology, and materials science.
A halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity.
"Definition of the halogen bond (IUPAC Recommendations 2013)" - Gautam R. Desiraju, P. Shing Ho, Lars Kloo, Anthony C. Legon, Roberto Marquardt, Pierangelo Metrangolo, Peter Politzer, Giuseppe Resnati and Kari Rissanen - Pure Appl. Chem., Vol. 85, No. 8, pp. 1711–1713, 2013.
WP 1: Design and synthesis of "smart" peptides and foldamers containing halogen bonding-donor groups
- Exploit halogen bonding for the design of "smart" peptides
- Amyloid fibril formation study of oligopeptides containing halogen bonding-donor groups
- Study the role of halogen bonding in the folding of proteins
WP 2: Crystal structure study of halogenated ligand/protein complexes
One of the advantages that halogen bonding has in this field over classical electrostatic, steric, and hydrogen bonding interactions is that halogen atoms in biological molecules are uncommon and, therefore, site-specific incorporation of halogen atoms into amino acids, oligopeptides, and proteins can confer a very high degree of control and specificity.
- Assessment of biomolecular recognition features of polyhalogenated persistent organic pollutants
- Crystal structure study of halogenated ligand/protein complexes
- Protein crystallography and complexation studies on halocarbon/protein adducts
WP 3: Biomimetic sensors of polyhalogenated organic pollutants
Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in a wide array of household products ranging from linens to electronic equipment. When released in the environment they are persistent organic pollutants (POPs). Since their structure is similar to the thyroid hormones T4 and T3, they are able to disrupt the human endocrine system.
We will develop:
- Synthetic receptors for halocarbons deposited as self-assembled monolayers (SAM) and imprinted SAM (iSAM)
- Biomimetic sensors based on anti-T3 and T4 Fab fragments
Unlocking the biochemistry underpinning the molecular recognition features of halogenated POPs will contribute to understand and develop new methodologies for their monitoring and bioremediation.
Halogenation alters physicochemical properties and enhances the potency of drugs and anaesthetics. However, explanations of the structure-activity effects of halogen substituents have been limited to considerations of membrane solubility, increased steric effects of halogen substituents on aromatic rings, and reduced metabolism.
The discoveries resulting from this project will impact many fields as diverse as molecular medicine, drug design, materials science and nanotechnology, and green technologies by changing the understanding of the halocarbons-biomolecules molecular recognition phenomena.