Intercalation as a means to suppress cyclization and promote polymerization of base-pairing oligonucleotides in a prebiotic world

Eric D. Horowitz, Aaron E. Engelhart, Michael C. Chen, Kaycee A. Quarles, Michael W. Smith, David G. Lynn, Nicholas V. Hud

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The RNA world hypothesis proposes that nucleic acids were once responsible for both information storage and chemical catalysis, before the advent of coded protein synthesis. However, it is difficult to imagine how nucleic acid polymers first appeared, as the abiotic chemical formation of long nucleic acid polymers from mononucleotides or short oligonucleotides remains elusive, and barriers to achieving this goal are substantial. One specific obstacle to abiotic nucleic acid polymerization is strand cyclization. Chemically activated short oligonucleotides cyclize efficiently, which severely impairs polymer growth. We show that intercalation, which stabilizes and rigidifies nucleic acid duplexes, almost totally eliminates strand cyclization, allowing for chemical ligation of tetranucleotides into duplex polymers of up to 100 base pairs in length. In contrast, when these reactions are performed in the absence of intercalators, almost exclusively cyclic tetra- and octanucleotides are produced. Intercalator-free polymerization is not observed, even at tetranucleotide concentrations >10; 000-fold greater than those at which intercalators enable polymerization. We also demonstrate that intercalation-mediated polymerization is most favored if the size of the intercalator matches that of the base pair; intercalators that bind to Watson-Crick base pairs promote the polymerization of oligonucleotides that form these base pairs. Additionally, we demonstrate that intercalation-mediated polymerization is possible with an alternative, non-Watson-Crick-paired duplex that selectively binds a complementary intercalator. These results support the hypothesis that intercalators (acting as 'molecular midwives') could have facilitated the polymerization of the first nucleic acids and possibly helped select the first base pairs, even if only trace amounts of suitable oligomers were available.

Original languageEnglish (US)
Pages (from-to)5288-5293
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number12
DOIs
StatePublished - Mar 23 2010

Fingerprint

Intercalating Agents
Prebiotics
Cyclization
Oligonucleotides
Base Pairing
Polymerization
Nucleic Acids
Polymers
Information Storage and Retrieval
Midwifery
Catalysis
Ligation
RNA
Growth

Keywords

  • Base pair selection
  • Molecular evolution
  • Origin of life
  • Polymerization
  • RNA world

Cite this

Intercalation as a means to suppress cyclization and promote polymerization of base-pairing oligonucleotides in a prebiotic world. / Horowitz, Eric D.; Engelhart, Aaron E.; Chen, Michael C.; Quarles, Kaycee A.; Smith, Michael W.; Lynn, David G.; Hud, Nicholas V.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 12, 23.03.2010, p. 5288-5293.

Research output: Contribution to journalArticle

Horowitz, Eric D. ; Engelhart, Aaron E. ; Chen, Michael C. ; Quarles, Kaycee A. ; Smith, Michael W. ; Lynn, David G. ; Hud, Nicholas V. / Intercalation as a means to suppress cyclization and promote polymerization of base-pairing oligonucleotides in a prebiotic world. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 12. pp. 5288-5293.
@article{847ccfcf9afe45d498067650c02c288d,
title = "Intercalation as a means to suppress cyclization and promote polymerization of base-pairing oligonucleotides in a prebiotic world",
abstract = "The RNA world hypothesis proposes that nucleic acids were once responsible for both information storage and chemical catalysis, before the advent of coded protein synthesis. However, it is difficult to imagine how nucleic acid polymers first appeared, as the abiotic chemical formation of long nucleic acid polymers from mononucleotides or short oligonucleotides remains elusive, and barriers to achieving this goal are substantial. One specific obstacle to abiotic nucleic acid polymerization is strand cyclization. Chemically activated short oligonucleotides cyclize efficiently, which severely impairs polymer growth. We show that intercalation, which stabilizes and rigidifies nucleic acid duplexes, almost totally eliminates strand cyclization, allowing for chemical ligation of tetranucleotides into duplex polymers of up to 100 base pairs in length. In contrast, when these reactions are performed in the absence of intercalators, almost exclusively cyclic tetra- and octanucleotides are produced. Intercalator-free polymerization is not observed, even at tetranucleotide concentrations >10; 000-fold greater than those at which intercalators enable polymerization. We also demonstrate that intercalation-mediated polymerization is most favored if the size of the intercalator matches that of the base pair; intercalators that bind to Watson-Crick base pairs promote the polymerization of oligonucleotides that form these base pairs. Additionally, we demonstrate that intercalation-mediated polymerization is possible with an alternative, non-Watson-Crick-paired duplex that selectively binds a complementary intercalator. These results support the hypothesis that intercalators (acting as 'molecular midwives') could have facilitated the polymerization of the first nucleic acids and possibly helped select the first base pairs, even if only trace amounts of suitable oligomers were available.",
keywords = "Base pair selection, Molecular evolution, Origin of life, Polymerization, RNA world",
author = "Horowitz, {Eric D.} and Engelhart, {Aaron E.} and Chen, {Michael C.} and Quarles, {Kaycee A.} and Smith, {Michael W.} and Lynn, {David G.} and Hud, {Nicholas V.}",
year = "2010",
month = "3",
day = "23",
doi = "10.1073/pnas.0914172107",
language = "English (US)",
volume = "107",
pages = "5288--5293",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "12",

}

TY - JOUR

T1 - Intercalation as a means to suppress cyclization and promote polymerization of base-pairing oligonucleotides in a prebiotic world

AU - Horowitz, Eric D.

AU - Engelhart, Aaron E.

AU - Chen, Michael C.

AU - Quarles, Kaycee A.

AU - Smith, Michael W.

AU - Lynn, David G.

AU - Hud, Nicholas V.

PY - 2010/3/23

Y1 - 2010/3/23

N2 - The RNA world hypothesis proposes that nucleic acids were once responsible for both information storage and chemical catalysis, before the advent of coded protein synthesis. However, it is difficult to imagine how nucleic acid polymers first appeared, as the abiotic chemical formation of long nucleic acid polymers from mononucleotides or short oligonucleotides remains elusive, and barriers to achieving this goal are substantial. One specific obstacle to abiotic nucleic acid polymerization is strand cyclization. Chemically activated short oligonucleotides cyclize efficiently, which severely impairs polymer growth. We show that intercalation, which stabilizes and rigidifies nucleic acid duplexes, almost totally eliminates strand cyclization, allowing for chemical ligation of tetranucleotides into duplex polymers of up to 100 base pairs in length. In contrast, when these reactions are performed in the absence of intercalators, almost exclusively cyclic tetra- and octanucleotides are produced. Intercalator-free polymerization is not observed, even at tetranucleotide concentrations >10; 000-fold greater than those at which intercalators enable polymerization. We also demonstrate that intercalation-mediated polymerization is most favored if the size of the intercalator matches that of the base pair; intercalators that bind to Watson-Crick base pairs promote the polymerization of oligonucleotides that form these base pairs. Additionally, we demonstrate that intercalation-mediated polymerization is possible with an alternative, non-Watson-Crick-paired duplex that selectively binds a complementary intercalator. These results support the hypothesis that intercalators (acting as 'molecular midwives') could have facilitated the polymerization of the first nucleic acids and possibly helped select the first base pairs, even if only trace amounts of suitable oligomers were available.

AB - The RNA world hypothesis proposes that nucleic acids were once responsible for both information storage and chemical catalysis, before the advent of coded protein synthesis. However, it is difficult to imagine how nucleic acid polymers first appeared, as the abiotic chemical formation of long nucleic acid polymers from mononucleotides or short oligonucleotides remains elusive, and barriers to achieving this goal are substantial. One specific obstacle to abiotic nucleic acid polymerization is strand cyclization. Chemically activated short oligonucleotides cyclize efficiently, which severely impairs polymer growth. We show that intercalation, which stabilizes and rigidifies nucleic acid duplexes, almost totally eliminates strand cyclization, allowing for chemical ligation of tetranucleotides into duplex polymers of up to 100 base pairs in length. In contrast, when these reactions are performed in the absence of intercalators, almost exclusively cyclic tetra- and octanucleotides are produced. Intercalator-free polymerization is not observed, even at tetranucleotide concentrations >10; 000-fold greater than those at which intercalators enable polymerization. We also demonstrate that intercalation-mediated polymerization is most favored if the size of the intercalator matches that of the base pair; intercalators that bind to Watson-Crick base pairs promote the polymerization of oligonucleotides that form these base pairs. Additionally, we demonstrate that intercalation-mediated polymerization is possible with an alternative, non-Watson-Crick-paired duplex that selectively binds a complementary intercalator. These results support the hypothesis that intercalators (acting as 'molecular midwives') could have facilitated the polymerization of the first nucleic acids and possibly helped select the first base pairs, even if only trace amounts of suitable oligomers were available.

KW - Base pair selection

KW - Molecular evolution

KW - Origin of life

KW - Polymerization

KW - RNA world

UR - http://www.scopus.com/inward/record.url?scp=77950379430&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950379430&partnerID=8YFLogxK

U2 - 10.1073/pnas.0914172107

DO - 10.1073/pnas.0914172107

M3 - Article

C2 - 20212163

AN - SCOPUS:77950379430

VL - 107

SP - 5288

EP - 5293

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 12

ER -