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RNAdualPF: software to compute the dual partition function with sample applications in molecular evolution theory.

ABSTRACT: RNA inverse folding is the problem of finding one or more sequences that fold into a user-specified target structure s 0, i.e. whose minimum free energy secondary structure is identical to the target s 0. Here we consider the ensemble of all RNA sequences that have low free energy with respect to a given target s 0.We introduce the program RNAdualPF, which computes the dual partition function Z ?, defined as the sum of Boltzmann factors exp(-E(a,s 0)/RT) of all RNA nucleotide sequences a compatible with target structure s 0. Using RNAdualPF, we efficiently sample RNA sequences that approximately fold into s 0, where additionally the user can specify IUPAC sequence constraints at certain positions, and whether to include dangles (energy terms for stacked, single-stranded nucleotides). Moreover, since we also compute the dual partition function Z ?(k) over all sequences having GC-content k, the user can require that all sampled sequences have a precise, specified GC-content. Using Z ?, we compute the dual expected energy ?E ??, and use it to show that natural RNAs from the Rfam 12.0 database have higher minimum free energy than expected, thus suggesting that functional RNAs are under evolutionary pressure to be only marginally thermodynamically stable. We show that C. elegans precursor microRNA (pre-miRNA) is significantly non-robust with respect to mutations, by comparing the robustness of each wild type pre-miRNA sequence with 2000 [resp. 500] sequences of the same GC-content generated by RNAdualPF, which approximately [resp. exactly] fold into the wild type target structure. We confirm and strengthen earlier findings that precursor microRNAs and bacterial small noncoding RNAs display plasticity, a measure of structural diversity.We describe RNAdualPF, which rapidly computes the dual partition function Z ? and samples sequences having low energy with respect to a target structure, allowing sequence constraints and specified GC-content. Using different inverse folding software, another group had earlier shown that pre-miRNA is mutationally robust, even controlling for compositional bias. Our opposite conclusion suggests a cautionary note that computationally based insights into molecular evolution may heavily depend on the software used. C/C++-software for RNAdualPF is available at http://bioinformatics.bc.edu/clotelab/RNAdualPF .

SUBMITTER: Garcia-Martin JA

PROVIDER: S-EPMC5069997 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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RNAdualPF: software to compute the dual partition function with sample applications in molecular evolution theory.

Garcia-Martin Juan Antonio JA Bayegan Amir H AH Dotu Ivan I Clote Peter P

BMC bioinformatics 20161019 1

<h4>Background</h4>RNA inverse folding is the problem of finding one or more sequences that fold into a user-specified target structure s <sub>0</sub>, i.e. whose minimum free energy secondary structure is identical to the target s <sub>0</sub>. Here we consider the ensemble of all RNA sequences that have low free energy with respect to a given target s <sub>0</sub>.<h4>Results</h4>We introduce the program RNAdualPF, which computes the dual partition function Z <sup>∗</sup>, defined as the sum o ...[more]

PMID: 27756204

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Project description:In this paper, we describe an automated integration-free path-integral (AIF-PI) method, based on Kleinert's variational perturbation (KP) theory, to treat internuclear quantum-statistical effects in molecular systems. We have developed an analytical method to obtain the centroid potential as a function of the variational parameter in the KP theory, which avoids numerical difficulties in path-integral Monte Carlo or molecular dynamics simulations, especially at the limit of zero-temperature. Consequently, the variational calculations using the KP theory can be efficiently carried out beyond the first order, i.e., the Giachetti-Tognetti-Feynman-Kleinert variational approach, for realistic chemical applications. By making use of the approximation of independent instantaneous normal modes (INM), the AIF-PI method can readily be applied to many-body systems. Previously, we have shown that in the INM approximation, the AIF-PI method is accurate for computing the quantum partition function of a water molecule (3 degrees of freedom) and the quantum correction factor for the collinear H(3) reaction rate (2 degrees of freedom). In this work, the accuracy and properties of the KP theory are further investigated by using the first three order perturbations on an asymmetric double-well potential, the bond vibrations of H(2), HF, and HCl represented by the Morse potential, and a proton-transfer barrier modeled by the Eckart potential. The zero-point energy, quantum partition function, and tunneling factor for these systems have been determined and are found to be in excellent agreement with the exact quantum results. Using our new analytical results at the zero-temperature limit, we show that the minimum value of the computed centroid potential in the KP theory is in excellent agreement with the ground state energy (zero-point energy) and the position of the centroid potential minimum is the expectation value of particle position in wave mechanics. The fast convergent property of the KP theory is further examined in comparison with results from the traditional Rayleigh-Ritz variational approach and Rayleigh-Schrödinger perturbation theory in wave mechanics. The present method can be used for thermodynamic and quantum dynamic calculations, including to systematically determine the exact value of zero-point energy and to study kinetic isotope effects for chemical reactions in solution and in enzymes.

Dataset Information

RNAdualPF: software to compute the dual partition function with sample applications in molecular evolution theory.

Publications

RNAdualPF: software to compute the dual partition function with sample applications in molecular evolution theory.

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