Building Molecular Machines with Biological Functions

Key words: Intermolecular bonding, hydrogen bonds, DNA, proteins, biomimicry, foldamers

Hydrogen bonds are among the most predominant and powerful non-covalent intermolecular interactions found in nature. They are typically weaker than covalent bonds, and stronger than Van der Waals (instantaneous dipole-dipole) interactions. Hydrogen bonding is responsible for countless natural phenomena, for example it participates to the binding of drugs to proteins, hydrogen bonds are involved in the self-organization of complex molecular systems such as the folding of proteins into their highly specific three-dimensional structures, which are vital to their physiological or biochemical function (figure 1). The double helical structure of DNA is largely due to the highly specific hydrogen bonding between the amine proton donors (-NH2 or -NH) and the carbonyl group (C=O) acceptors of the paired nitrogenous bases.

Figure 1. Hydrogen bonds in the self-organization of DNA, and proteins

Biological information is encoded in DNA or RNA by two dimensional arrangements of hydrogen bond donors and acceptors in nucleotide sequences. Taking our inspiration for research from nature, we aim to build artificial ‘biomimetic’ molecular machines that read information encoded by similar arrangements of hydrogen bond donors and acceptors, communicate information through a small space, and translate it into a chemical feature at a site remote (nanometre distance) from the informational source.

Our molecular machine is a ‘foldamer’ composed of 3 parts: (1) an artificial receptor designed to read information contained in ligands by molecular recognition of their hydrogen-bond donor/acceptor arrangement, (2) a chain of hydrogen-bonded functional groups forming a hydrogen-bond network that is switchable in directionality (direction in which the functional groups point), (3) an effector than can be activated/deactivated to catalyse a chemical reaction at a nanometre distance from the artificial receptor (figure 2). Given the expected tendency of the hydrogen bonds to form a continuous network throughout the length of the chain of the foldamer, we expect it to be possible to orientate the whole hydrogen-bond network between the two alternative directionalities, by inducing one end of the chain to switch between being a hydrogen bond acceptor to a hydrogen bond donor. The binding of ligands at one extremity of the foldamer will switch the directionality of the entire hydrogen-bond network and activate/deactivate the effector at the other extremity of the foldamer to catalyse a reaction.

Incoming ligand Receptor Effector Reaction (catalysed or not)

catalyses reaction

doesn’t catalyse reaction

Figure 2. Our design of molecular machine

Our device should be able to mimic the fundamental functions of biological systems and behave as synthetic analogues of proteins involved in signalling with cells. It could find use in a wide range of medicinal applications as it could potentially replace defective transmembrane proteins and restore the capacity to communicate information through cell membranes, cellular functions that would otherwise give rise to disease (figure 3).

Figure 3. Analogues of proteins involved in signal transduction

David Tilly completed a Ph.D. in Organic Chemistry at Université du Maine (France), working on directed lithiations of aromatic rings (with Prof. J. Mortier and Prof. V. Snieckus). He then worked as a postdoctoral fellow on multistep syntheses of complex natural products (with Assoc. Prof. C. Williams, University of Queensland, Brisbane, Australia), on the development of anticancer drugs based on natural product scaffolds (with Assoc. Prof. Coster, ESKITIS Institute for Drug Discovery, Brisbane, Australia), on catalyzed C–H bond functionalizations (with Prof. V. Gevorgyan, University of Illinois, USA), on asymmetric synergetic bimetallic ‘ate

combinations for synthesis (with Prof. F. Mongin, Université de Rennes, France), on radioimmunoconjugates of astatine-211 (with Prof. Deniaud, Université de Nantes, France), then as a lecturer (term position, Université de Rennes). He is currently working as a Marie Skłodowska-Curie Fellow at the University of Bristol in the group of Prof. Jonathan Clayden, where he is developing molecular machines with biological functions.

Building Molecular Machines with Biological Functions

Questions

1. Draw a diagram of a hydrogen bond formed between amine proton donors (-NH2) and the carbonyl group (C=O) acceptor. [2 marks]

2. List 4 electronegative elements that can be involved in hydrogen bonding. [2 marks]3. Draw the arrangement of atoms in the peptide link that bonds amino acids together to make

proteins. [2 marks]4. What does ‘DNA’ stand for? [1 mark]5. What is a ligand? [1 mark]6. How many nanometres in a metre? [1 mark]

Building Molecular Machines with Biological Functions

Questions

1. Draw a diagram of a hydrogen bond formed between amine proton donors (-NH2) and the carbonyl group (C=O) acceptor. [2 marks]

2. List 4 electronegative elements that can be involved in hydrogen bonding. [2 marks]

3. Draw the arrangement of atoms in the peptide link that bonds amino acids together to make proteins. [2 marks]

4. What does ‘DNA’ stand for? [1 mark]

5. What is a ligand? [1 mark]

6. How many nanometres in a metre? [1 mark]