Theme 1: Synthesis of Nanomachines in the Origin of Life

Theme 1 seeks to understand how complex extant nanomachines that catalyze electron transfer emerged from simple prebiotic chemical processes.  Two possible biochemical origins scenarios will be explored: on the early Earth at the beginning of the Archean eon, and on other planets where different amino acid alphabets and chemical constraints might likely be present.  Central to both scenarios is the hypothesis that the first functional molecules were small low-complexity metal-binding peptides that were capable of primitive electron transfer and catalysis, and that these functional peptides subsequently evolved into larger proteins.  Since no direct physical fossils of these earliest peptides exist, we will instead turn to databases containing thousands of high resolution extant protein structures and powerful computer simulation tools for engineering small peptides from basic physical principles. This will essentially re-invent plausible candidates for early-life peptides.


In Theme 1, terrestrial peptides will be constructed from the twenty natural amino acids, whereas extraterrestrial peptides will incorporate a much broader alphabet, informed by amino acid distributions found in meteorites and prebiotic chemical simulations such as the classic Urey-Miller experiments. Early peptides are proposed to have assembled into circuits capable of conducting electricity where electron transfer occurred primarily through the metals coordinated by peptides.  Thus, it would be critical for peptides to preserve structure and metal binding as these sites assume transient oxidized or reduced excited states.  In order to assess their functional potential, candidate molecules will be synthesized and tested for metal binding using a number of spectroscopic, scattering and microscopy methods.  High resolution structures will be determined by X-ray diffraction and solution NMR methods to ascertain how similar early peptides are to subsets of extant oxidreductases.  A series of functional assays that range from electron transfer and catalysis to the ability to act as metabolic surrogates will be used to evaluate the functional capacity of these small peptides.  The resulting peptide designs will be used to root protein evolutionary trees and to inform powerful machine learning tools that will link information gathered on early peptides, extant proteins and Earth’s geochemical cycles across all three Themes.