Secondary structure formation of homopolymeric single-stranded nucleic acids including force and loop entropy: implications for DNA hybridization

TL;DR

This paper develops a theoretical model for homopolymeric single-stranded nucleic acids that incorporates loop entropy and external force, revealing phase transitions and effects on DNA hybridization and melting behavior.

Contribution

It introduces a new analytical framework accounting for logarithmic loop entropy and force effects, extending understanding of nucleic acid secondary structure phase transitions.

Findings

Phase transition between folded and unfolded states depends on loop exponent c.

Force-induced melting transition occurs for all c < 2.479 and is experimentally observable.

Secondary structures inside single strands lower duplex melting temperature and influence transition universality.

Abstract

Loops are essential secondary structure elements in folded DNA and RNA molecules and proliferate close to the melting transition. Using a theory for nucleic acid secondary structures that accounts for the logarithmic entropy c ln m for a loop of length m, we study homopolymeric single-stranded nucleic acid chains under external force and varying temperature. In the thermodynamic limit of a long strand, the chain displays a phase transition between a low temperature / low force compact (folded) structure and a high temperature / high force molten (unfolded) structure. The influence of c on phase diagrams, critical exponents, melting, and force extension curves is derived analytically. For vanishing pulling force, only for the limited range of loop exponents 2 < c < 2.479 a melting transition is possible; for c <= 2 the chain is always in the folded phase and for 2.479 < c always in the unfolded phase. A force induced melting transition with singular behavior is possible for all loop exponents c < 2.479 and can be observed experimentally by single molecule force spectroscopy. These findings have implications for the hybridization or denaturation of double stranded nucleic acids. The Poland-Scheraga model for nucleic acid duplex melting does not allow base pairing between nucleotides on the same strand in denatured regions of the double strand. If the sequence allows these intra-strand base pairs, we show that for a realistic loop exponent c ~ 2.1 pronounced secondary structures appear inside the single strands. This leads to a lower melting temperature of the duplex than predicted by the Poland-Scheraga model. Further, these secondary structures renormalize the effective loop exponent c^, which characterizes the weight of a denatured region of the double strand, and thus affect universal aspects of the duplex melting transition.