Two papers on the fundamental principles of biomolecular copying

Single cells, which are essentially bags of chemicals, can achieve remarkable feats of information processing. Humans have designed computers to perform similar tasks in our everyday world. The question of whether it is possible to emulate cells and use molecular systems to perform complex computational tasks in parallel, at an extremely small scale and consuming a low amount of power, is one that has intrigued many scientists.

In collaboration with the ten Wolde group from AMOLF Amsterdam, we have just published two articles in Physical Review X and Physical Review Letters that get to the heart of this question. 

The readout molecules (orange) act as copies of the binding
state of the receptors (purple), through catalytic
phosphorylation/dephosphorylation reactions.

In the first, “The Thermodynamics of computational copying in biochemical systems”, we show that a simple molecular process occurring inside living cells - a phosphorylation/dephosphorylation cycle - is able to copy the state of one protein (for example, whether a food molecule is bound to it or not) into the chemical modification state of another protein (phosphorylated or not). This copy process can be rigorously related to those performed by conventional computers.

We thus demonstrated that living cells can perform the basic computational operation of copying a single bit of information. Moreover, our analysis revealed that these biochemical computations can occur rapidly and at a low power consumption. The article shows precisely how natural systems relate to and differ from traditional computing architectures, and provides a blueprint for building naturally-inspired synthetic copying  systems that approach the lower limits of power consumption.

The production of a persistent copy from a template.
The separation in the final state is essential.

A more complex natural copy operation is the production of polymer copies from polymer templates, as discussed in this previous post. Such processes are necessary for DNA replication, and also for the production of proteins from DNA templates via intermediate RNA molecules. For cells to function, the data in the original DNA sequence of bases must be faithfully reproduced - each copy therefore involves copying many bits of data. 

In the second article, "Fundamental costs in the production and destruction of persistent polymer copies", we consider such processes. We point out that these polymer copies must be persistent to be functional. In other words, the end result is two physically separate polymers: it would be useless to produce proteins that couldn't detach from their nucleic acid templates. As a result, the underlying principles are very different from the superficially similar process of self-assembly, in which molecules aggregate together according to specific interactions to form a well-defined structure. 

In particular, we show that the need to produce persistent copies implies that more accurate copies necessarily have a higher minimal production cost (in terms of resources consumed) than sloppier copies. This result, which is not true if the copies do not need to physically separate from their templates, sets a bound on the function of minimal self-replicating systems.

Additionally, the  results suggest that polymer copying processes that occur without external intervention (autonomously) must occur far from equilibrium. Being far from equilibrium means that processes are highly irreversible - taking a forwards step is much more likely than taking a backwards step. This finding draws a sharp distinction with self-assembling systems, that typically assemble most accurately when close to equilibrium. This difference may explain why recent years have shown an enormous growth in the successful design of self-assembling molecular systems, but autonomous synthetic systems that produce persistent copies through chemical means have yet to be constructed.

Taken together, these papers set a theoretical background on which to base the design of synthetic molecular systems that achieve computational processes such as copying and information transmission. The next challenge is now to develop experimental systems that exploit these ideas.