A new entropy model for RNA: part I. A critique of the standard Jacobson-Stockmayer model applied to multiple cross links

Abstract

The Jacobson-Stockmayer (JS) model is used in a number of standard programs for calculating the conformational entropy of RNA (and proteins). However, it is shown in this study that, in certain limiting cases, the current form of this model can lead to highly unphysical conclusions. The origin of this behavior can be traced to misunderstandings that occurred during the development of the model as applied to folded, single-stranded RNA. Here we show that an alternative model known as the cross linking entropy (CLE) model can overcome these issues. The principal object that causes entropy loss on a global scale in the CLE model is the stem, the primary measure of structural order in such coarse-grained calculations. The principal objects in the JS-model are various types of loops, and, with the exception of the hairpin loop, they are topologically local in character. To extract experimentally measurable variables, a simplified version of the CLE model is developed that resembles many features of the contact order model used in RNA and protein folding. These modifications are then applied to single molecule force-extension experiments (molecular tweezers) to extract quantitative information. It is further shown that a crude derivative of the CLE model itself can be derived directly from the JS-model when the misunderstandings are examined and corrected.

Ribozyme Activity of RNA Nonenzymatically Polymerized from 3′,5′-Cyclic GMP

“…The Tm of G-C double-stranded oligonucleotides was calculated using the Crosslinking Entropy (CLE) Method [45,46]. According to this method the Tm of these molecules at the concentration here used of 1.3 M is, when fully paired, 86 °C.…”

Describing the Structural Diversity within an RNA’s Ensemble

“…Many of the current programs even have the ability to return the partition function and perform suboptimal sampling for a given RNA sequence [37][38][39][40][41]. Recent work has pushed beyond simple energy calculations to include entropic modifications to the folding algorithms [42]. A complete discussion of the procedure of how these programs work is beyond the scope of this paper, but can be found elsewhere [30,43,44].…”

“…This target structure, S 0 , may be any structure the RNA sequence can fold into, including, but not limited to, predicted structures from standard dynamic programing [28,38,40,41], structures predicted using more sophisticated methods [42] or identified crystal structures. The ensemble defect was originally used to measure the success of designing a sequence that would take on a desired structure [51][52][53].…”