Abstract

The development of approaches for predictive calculation of hybridization properties of various nucleic acid (NA) derivatives is the basis for the rational design of the NA-based constructs. Modern advances in computer modeling methods provide the feasibility of these calculations. We have analyzed the possibility of calculating the energy of DNA/RNA and RNA/RNA duplex formation using representative sets of complexes (65 and 75 complexes, respectively). We used the classical molecular dynamics (MD) method, the MMPBSA or MMGBSA approaches to calculate the enthalpy (ΔH°) component, and the quasi-harmonic approximation (Q-Harm) or the normal mode analysis (NMA) methods to calculate the entropy (ΔS°) contribution to the Gibbs energy (Delta G_{{37}}^{^circ } ) of the NA complex formation. We have found that the MMGBSA method in the analysis of the MD trajectory of only the NA duplex and the empirical linear approximation allow calculation of the enthalpy of formation of the DNA, RNA, and hybrid duplexes of various lengths and GC content with an accuracy of 8.6%. Within each type of complex, the combination of rather efficient MMGBSA and Q-Harm approaches being applied to the trajectory of only the bimolecular complex makes it possible to calculate the Delta G_{{37}}^{^circ } of the duplex formation with an error value of 10%. The high accuracy of predictive calculation for different types of natural complexes (DNA/RNA, DNA/RNA, and RNA/RNA) indicates the possibility of extending the considered approach to analogs and derivatives of nucleic acids, which gives a fundamental opportunity in the future to perform rational design of new types of NA-targeted sequence-specific compounds.

Highlights

  • Derivatives and analogs of nucleic acids (NA) are used to solve the problems of targeted therapy of various diseases [1, 2], biosensor technologies, molecular biology [3], and biotechnology [4]

  • The creation of new derivatives with predetermined biological and physicochemical properties remains an urgent task in Abbreviations: MD, molecular dynamics; NA, nucleic acid; MMGBSA (Molecular Mechanics/Generalized Born Surface Area), a component-by-component approach for calculating the free energy change based on simulation by the molecular dynamics method using the generalized Born model; MMPBSA (Molecular Mechanics/Poisson Boltzmann Surface Area), a component-by-component method for calculating the free energy change based on a molecular dynamics simulation using the Poisson-Boltzmann model; normal mode analysis (NMA) (Normal Mode Analysis), analysis of normal modes of oscillation; quasi-harmonic approximation (Q-Harm), QuasiHarmonic approximation

  • We have previously shown that computer calculations for evaluating the hybridization properties of DNA/DNA duplexes provide accuracy comparable to that of experimental methods [30]

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Summary

Introduction

Derivatives and analogs of nucleic acids (NA) are used to solve the problems of targeted therapy of various diseases [1, 2], biosensor technologies, molecular biology [3], and biotechnology [4]. The creation of new derivatives with predetermined biological and physicochemical properties remains an urgent task in Abbreviations: MD, molecular dynamics; NA, nucleic acid; MMGBSA (Molecular Mechanics/Generalized Born Surface Area), a component-by-component approach for calculating the free energy change based on simulation by the molecular dynamics method using the generalized Born model; MMPBSA (Molecular Mechanics/Poisson Boltzmann Surface Area), a component-by-component method for calculating the free energy change based on a molecular dynamics simulation using the Poisson-Boltzmann model; NMA (Normal Mode Analysis), analysis of normal modes of oscillation; Q-Harm, QuasiHarmonic approximation. There are no methods for evaluating the hybridization properties of NA derivatives before chemical synthesis. In the case of new compounds, it is necessary to use approaches that do not rely on experimental information on their hybridization properties. Methods based on molecular mechanics and/or molecular dynamics (MD) are suitable for large compounds consisting of more than 100 atoms

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