# Selection for Molecularly Complementary Modules (MCMs) Drives the Origins and Evolution of Pleiofunctional, Epistatic Interactomes (PEIs)

## TL;DR

This paper proposes that molecularly complementary modules drive the evolution of complex cellular networks by enabling stability and new functions through combination.

## Contribution

The novel hypothesis is that MCMs are selected for stability and combine to form pleiofunctional, epistatic interactomes.

## Key findings

- MCMs can mix and match to create novel molecules with emergent properties.
- Case studies show MCMs underpin the evolution of antioxidant systems and ribosomes.
- MCM-based systems retain historical clues about their evolutionary origins.

## Abstract

The huge number of possible permutations of genes, proteins and small molecules make the random emergence of cellular networks problematic. How, therefore, do interactomes come into existence? What selects for their stability and functionality? I hypothesize that interactomes originate from molecularly complementary modules (MCMs) that are selected for stability and retain their interactivity when mixed and matched with other such modules to create novel molecules and complexes displaying emergent properties not present in the individual components of the network. Because evolution can only proceed by working upon existing variants, and these variants emerge from selection of MCMs, the resulting systems must exhibit the characteristics of pleiofunctional, epistatic interactomes (PEIs). The resulting systems should display “molecular paleontology”, providing clues as to the historical process by which these MCMs were incorporated into the system. The MCM mechanism of PEI evolution is illustrated here by two case studies. The first concerns the prebiotic emergence of the glutathione–ascorbate anti-oxidant system and its later incorporation into regulation of glucose transport and catecholamine receptor activity. The second concerns the MCM evolution of the ribosome as, perhaps, the first PEI, and its role as a module for the later construction of the first cellular genomes.