Length-Selective Synthesis of Acylglycerol-Phosphates through Energy-Dissipative Cycling

Abstract

The main aim of origins of life research is to find a plausible sequence of transitions from prebiotic chemistry to nascent biology. In this context, understanding how and when phospholipid membranes appeared on early Earth is critical to elucidating the prebiotic pathways that led to the emergence of primitive cells. Here we show that exposing glycerol-2-phosphate to acylating agents leads to the formation of a library of acylglycerol-phosphates. Medium-chain acylglycerol-phosphates were found to self-assemble into vesicles stable across a wide range of conditions and capable of retaining mono- and oligonucleotides. Starting with a mixture of activated carboxylic acids of different lengths, iterative cycling of acylation and hydrolysis steps allowed for the selection of longer-chain acylglycerol-phosphates. Our results suggest that a selection pathway based on energy-dissipative cycling could have driven the selective synthesis of phospholipids on early Earth.

Scheme 1. Reaction Pathway That Leads to Synthesis of C2–C10 Alcohols, Aldehydes, and Carboxylic Acids

For details, see SI.

Figure 1

Synthesis of acylglycerol-2-phosphates. (a) ³¹P NMR Spectra of the products of the described reactions. Glycerol-2-phosphate 7 is highlighted in orange, monoacylated species 9a–d and 9f are highlighted in blue, and bis-acylated species 10a–d and 10f are highlighted in green. (b) Reaction yields for the synthesis of mono- and bis-acylglycerol-2-phosphate derivatives.

Scheme 2. Proposed Mechanism for the Synthesis of Acylglycerol-Phosphates

Figure 2

Membrane self-assembly of acylglycerol-2-phosphates. (a–c) Vesicles were observed in crude mixtures of mono- and bis-acylglycerol-2-phosphates (pH 7.4, estimated lipid concentration: ∼40 mM): (a) 9d and 10d; (b) 9e and 10e; (c) 9f and 10f. (d) pH Stability range for vesicles made of pure 10d–f. (e) Temperature stability of vesicles made of 1:1 mixtures of 9d–f and 10d–f.

Figure 3

Selective accumulation of prebiotic phospholipids via energy-dissipative cycling. (a) Scheme of the acylation–hydrolysis cycles. (b) Stability of 10a–d toward hydrolysis. (c) Membranes made of mixed acylglycerol-2-phosphates were observed from the second acylation–hydrolysis round.