Periodic Reporting for period 3 - DOGMATRON (Artificial Translation with Dynamic Foldamers: Relaying Encoded Messages into Chemical Function)
Periodo di rendicontazione: 2023-10-01 al 2025-03-31
Although biological systems are built from chemical structures, biology is differentiated from chemistry by information, manifested in the immense complexity of biological systems. Information in advanced human technologies is stored and manipulated electronically; in biology, information is stored in molecular (nucleic acid) structure is converted into molecular (protein) function by way of ribosomal translation and further manipulated through dynamic molecular interactions. Information-rich biology thus relies on chemical mechanisms for replicating, amplifying, and manipulating this information to allow global, integrated control of biochemical function, but the molecular structures involved in this manipulation of information are complex and highly evolved for specific functions.
We propose to devise new, biologically-inspired ways of using much simpler synthetic molecules – dynamic foldamers – to translate physical and chemical signals (eg molecular polarity, ligand structure light, pH, metal ions) into useful chemical and biochemical responses (catalysis, protein function, macroscopic properties of surfaces and vesicles) using molecular properties of selective recognition, switchable shape and conformational relay.
We propose to apply the power of synthetic chemistry to a new challenge in synthetic biomimicry: the translation of encoded information into molecular function. We propose to design and build switchable synthetic molecules that are capable of communicating and processing information. This ambitious aim will be achieved through new classes of extended dynamic molecules that respond to their environment by changing shape, principally by invertase polarity/directionality. They will receive, communicate, amplify, transmit, and process information encoded in their molecular conformation and orientation. New analystic methods will be developed to explore their kinetics and thermodynamics. Characterized by a high level of intramolecular structural organization, they will participate in strong, selective mutual interactions, allowing them to process information through intramolecular and intermolecular interactions in simple and complex mixtures, both solution and in the membrane phase. These chemical systems will be able to extract information from their environment (the presence of a specific metal or organic molecule, a genetically encoded message, pH, or irradiation at a specific wavelength) and process it into chemical function. Life takes information in the form of bond polarity encoded in base pairs and translates it into biochemical function in the form of protein structure, and our synthetic structures will likewise translate molecular polarity into function by using new classes of ‘promiscuous’ Watson-Crick-like base-pairs, able to switch between alternative hydrogen-bond polarities. Applications for these synthetic communication systems will ultimately see them embedded into cell membranes, allowing the selective control of function by communicating into the interior of both artificial vesicles and living cells.
Biological systems are built from a relatively limited selection of chemical structures. The field of foldamer chemistry has developed in response to this limitation, seeking to find artificial molecular motifs that mimic those found in biology. Foldamers are by definition conformationally defined structures, but in their classical form they cannot be used to build truly biomimetic systems because they lack the dynamic responsiveness characteristic of biological molecules. By combining biology's information storage and replication strategies with the new families of directionally-reversible dynamic foldamers that we propose to design and construct, we will pioneer new mechanisms for communicating and processing information in increasingly complex chemical systems. These systems will encode information in the form of molecular structure and use chemical interactions to process it in complex mixtures and communicate it through impermeable barriers. We propose to open up a new paradigm in science, allowing information to be processed using molecules rather than electronics.
Although the chemical components of biological systems have been studied extensively by the tools of chemistry, the complexity of a living cell lies well beyond even the most complex constructs of systems chemistry. Despite the constraints on the chemistry that biology can use, natural selection generates complexity from metabolic catalysts that must be encoded in nucleic acids and translated by the ribosome into amide polymers of just 20 alternative monomer units. Chemistry is not constrained in the same way, and with the periodic table as a toolkit, chemists can approach catalysis and synthesis from much more diverse angles. For example, the total synthesis of natural products takes the spectacular achievements of biosynthesis and deconstructs them, working out artificial ways to build those same molecules simply and conveniently. Conceptually, we take a parallel approach: we want to achieve the total synthesis of natural function. Noting the way that biology exploits molecular shape and interaction in the mechanisms of signal transduction and communication, we will take on the challenge of building artificial chemical systems that function similarly without the need to use nature's chemical repertoire
We propose to devise new, biologically-inspired ways of using much simpler synthetic molecules – dynamic foldamers – to translate physical and chemical signals (eg molecular polarity, ligand structure light, pH, metal ions) into useful chemical and biochemical responses (catalysis, protein function, macroscopic properties of surfaces and vesicles) using molecular properties of selective recognition, switchable shape and conformational relay.
We propose to apply the power of synthetic chemistry to a new challenge in synthetic biomimicry: the translation of encoded information into molecular function. We propose to design and build switchable synthetic molecules that are capable of communicating and processing information. This ambitious aim will be achieved through new classes of extended dynamic molecules that respond to their environment by changing shape, principally by invertase polarity/directionality. They will receive, communicate, amplify, transmit, and process information encoded in their molecular conformation and orientation. New analystic methods will be developed to explore their kinetics and thermodynamics. Characterized by a high level of intramolecular structural organization, they will participate in strong, selective mutual interactions, allowing them to process information through intramolecular and intermolecular interactions in simple and complex mixtures, both solution and in the membrane phase. These chemical systems will be able to extract information from their environment (the presence of a specific metal or organic molecule, a genetically encoded message, pH, or irradiation at a specific wavelength) and process it into chemical function. Life takes information in the form of bond polarity encoded in base pairs and translates it into biochemical function in the form of protein structure, and our synthetic structures will likewise translate molecular polarity into function by using new classes of ‘promiscuous’ Watson-Crick-like base-pairs, able to switch between alternative hydrogen-bond polarities. Applications for these synthetic communication systems will ultimately see them embedded into cell membranes, allowing the selective control of function by communicating into the interior of both artificial vesicles and living cells.
Biological systems are built from a relatively limited selection of chemical structures. The field of foldamer chemistry has developed in response to this limitation, seeking to find artificial molecular motifs that mimic those found in biology. Foldamers are by definition conformationally defined structures, but in their classical form they cannot be used to build truly biomimetic systems because they lack the dynamic responsiveness characteristic of biological molecules. By combining biology's information storage and replication strategies with the new families of directionally-reversible dynamic foldamers that we propose to design and construct, we will pioneer new mechanisms for communicating and processing information in increasingly complex chemical systems. These systems will encode information in the form of molecular structure and use chemical interactions to process it in complex mixtures and communicate it through impermeable barriers. We propose to open up a new paradigm in science, allowing information to be processed using molecules rather than electronics.
Although the chemical components of biological systems have been studied extensively by the tools of chemistry, the complexity of a living cell lies well beyond even the most complex constructs of systems chemistry. Despite the constraints on the chemistry that biology can use, natural selection generates complexity from metabolic catalysts that must be encoded in nucleic acids and translated by the ribosome into amide polymers of just 20 alternative monomer units. Chemistry is not constrained in the same way, and with the periodic table as a toolkit, chemists can approach catalysis and synthesis from much more diverse angles. For example, the total synthesis of natural products takes the spectacular achievements of biosynthesis and deconstructs them, working out artificial ways to build those same molecules simply and conveniently. Conceptually, we take a parallel approach: we want to achieve the total synthesis of natural function. Noting the way that biology exploits molecular shape and interaction in the mechanisms of signal transduction and communication, we will take on the challenge of building artificial chemical systems that function similarly without the need to use nature's chemical repertoire
So far, we have managed to design molecular structures that have defined shape, and have shown that the shapes can be modified in a number of different ways (pH changes, ligand binding, photo switching) allowing us to communicate information from one end of a molecule to the other. We have explored the dynamics of the changes of shape involved, and have shown that they are coherent, and that they can thus carry information reliably. Informational outputs have been included changes in conformational features and consequent spectroscopic reporters, or the release of a messenger into solution. Although all of the work has been in solution, the key functional parts of our system have been shown to operate successfully.
The communication of information through dynamic foldamers has previously been used to modulate spectroscopic features or to change the selectivity of a reaction. The ability to control the binding release of a ligand or to switch on or off reactivity is a new feature in the field. From our work on helical peptides, we have managed to devise a new peptide architecture that has the potential to add a significant new facet to the field of protein engineering. Exploration of out of equilibrium systems is also under way, and we expect a significant advance beyond the state of the art in this area within the next few months. The immediate challenge is to move out of the solution phase and to achieve function within myself and membranes, and ultimately to control the behaviour of cells and cell-like objects.