Towards the Idea of Molecular Brains
Well-documented structural studies have provided valuable insights into how either enzymes or receptors have developed sophisticated mechanisms to integrate multiple signals from remote sites: multisite allosteric enzymes and a dual-sensor histidine kinase. These studies help to decipher the general principles of signal integration at the molecular levels and provide structural and dynamical insights that may contribute to elucidating the intertwined molecular mechanisms of information transfer and processing in “molecular brains”. Enzymatic multisite allostery and receptor allosteric modulation share similar features that are described here. Multisite allostery or synergistic allostery allows enzymes to integrate and modulate their catalytic properties according to the presence of several substrates. A well-characterised example is the 3-deoxy-D-arabino heptulosonate 7-phosphate synthase (DAH7PS) of Mycobacterium tuberculosis, the first enzyme of the shikimate pathway, a metabolic pathway responsible for the aromatic amino acids [535]. This tetrameric enzyme whose monomer adopts a TIM-barrel fold possess distinct and remote allosteric sites for each aromatic Trp, Phe and Tyr amino acids. Their individual or combinatory binding affects differently the catalytic activity [536,537,538,539]. Interestingly, the structures of the free and ligand-bound enzymes do not display significant structural change suggesting that the allostery proceeds with the modification of the backbone dynamics. These works performed in Emily Parker’s lab are very valuable because it allows us to follow in detail the structural mechanisms at the origin of the integration of these multiple signals.
On the other hand, many receptors are allosterically are regulated by two inter-related sites. The activation of the orthosteric site by the orthosteric ligand is modulated by the allosteric site, which binds the allosteric modulators [286,307]. The binding of the ligands on the two remote sites modulates the receptor activation and the downstream cell signalling cascade. A recent dynamic crystallographic study on a dual-sensor histidine kinase has deciphered the allosteric mechanisms underlying the integration of its perception of light and phosphorylation signals. This system that combines a set of sensory and allosteric modules operates a molecular logic OR [540]. Interestingly these multi-sensor proteins share many structural and dynamical features found in r-protein networks. First, they combine diverse interacting sensor and allosteric modules that use different mechanisms for sensing and propagating signals. Second, these modules that have probably co-evolved for integrating multiple signals have acquired highly conserved aromatic residues that play critical and perhaps still not well-understood roles in both information transfer and processing [46]. For example, particular motifs formed between aromatic and charged residues (such as cation-π) mediate the communication between the allosteric modules or form the “ligand-binding pocket” in most of the membrane receptors [310,541] (Figure 8).
Third, in both the study of r-protein networks and receptors, many experimental observations do not always support a classical view of allostery. For example, allosteric ON/OFF switches often cannot be distinguished by marked structural differences in many receptors in different ribosomal functional states [45]. Furthermore, loose dynamical coupling is observed between domains that are supposed to cooperate [17]. Together, these observations suggest other types of allosteric mechanisms in which aromatic amino acids are involved in the propagation of electrostatic perturbations or charge transfer through their π electrons [45], as in nanowires [542] or DNA [543]. Thus, the structural motifs formed by the combination of aromatics and charged amino acids could give rise to subtle modulations of the signals that transit along proteins and play a critical role in both the transfer and integration of these signals. Could the structural analogy between neural networks and protein networks also be continued on a dynamic level? Could there be, for example, like the “neural code” based on the information contained in spike trains, an “allosteric code” at the basis of information processing in molecular networks? This question opens new perspectives on allosteric mechanisms and could initiate the exploration of a new paradigm.
And to close the loop, the cryptochromes of monarch butterflies bring quantum mechanics into biology thanks to their tryptophan clusters and their π-electrons [8,9]. Thus, aromatic amino acids have properties that are still underestimated, and in the light of their critical and still poorly understood role in allosteric processes, it does not seem unreasonable to us to imagine that they contribute to the processing of information through quantum phenomena [65]. These findings may provide useful insights for designing organic processors for the computers of the future.
From its earliest forms of organisation, life has had to accommodate and adapt to incessant fluctuations coming from both its internal activity and the external environment. Thus, in addition to its properties of self-organisation [544,545] and self-replication, which are considered its essence, life has had to develop complex behaviours from its origins, and its “first wills” already needed a “molecular brain”. Perceiving and integrating various signals and responding to them by taking appropriate decisions to survive and eventually prosper is, therefore, an indispensable faculty for all forms of life, regardless of its degree of organisation. Thus, when considering the “emergence of consciousness” from a molecular network, the two questions “what is the soul (the psychès of Aristotle) and what is life” may converge into one and the same and unique question.