Calculation of Energy for RNA/RNA and DNA/RNA Duplex Formation by Molecular Dynamics Simulation

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.

Modeling Peptide Nucleic Acid Binding Enthalpies Using MM-GBSA

“…This was possible since, for the binding enthalpy, the experimental error was approximately equal to a typical experimental error of 10%. 13 MM-GBSA enthalpies for all 49 sequences (Table S3) were used to solve the generalized multiple linear regression problem in eqs 5c−7a. Nearest-neighbor stacking, initiation, and terminal GC enthalpies were thus determined (Table 2).…”

“…Since the binding entropy, and therefore free energy, quantitatively disagreed with thermal melting data, a nearest-neighbor model was generated solely for the binding enthalpy. This was possible since, for the binding enthalpy, the experimental error was approximately equal to a typical experimental error of 10% …”

“…So long as these considerations are taken into account, the model can be highly predictive of real-world measurements. This was the case for previous research on MM-GBSA estimates of DNA and RNA …”

“…This was the case for previous research on MM-GBSA estimates of DNA and RNA. 13 In this research, corrected MM-GBSA data were not used for fitting the nearest-neighbor model so as to maximize the likelihood that sequence parameters were meaningful. Since the binding entropy, and therefore free energy, quantitatively disagreed with thermal melting data, a nearest-neighbor model was generated solely for the binding enthalpy.…”

Thermodynamic Swings: How Ideal Complex of Cas9–RNA/DNA Forms

“…It is important to note that the MM-GBSA method for calculating the energies of nucleic acid interaction has an error rate of ~9%, whereas MM-PBSA can give a significant errors in absolute values of enthalpy changes [ 41 ]. Despite this, the binding energies calculated by the MM-PBSA and MM-GBSA methods highly correlate, with R 2 = 0.99 ( Figure S4 ).…”