On the conformational stability of oligonucleotide duplexes and tRNA molecules.

Thermodynamic experiments provide a wealth of data about the conformational stability, viz., the free energy difference (delta G) between folded and unfolded states of DNA/RNA duplexes. However, there is no acceptable view about how the various non-covalent forces contribute individually to the observed stability. In particular, the role of the hydrophobic force is not clearly known. In this paper we quantitatively enumerate the stability factors, hydrogen bonding, base stacking, van der Waals, electrostatic, and hydrophobic interactions from the knowledge of the crystal structures of 15 DNA/RNA duplexes and two tRNA molecules, and translate them into free energy contributions to the stability of nucleic acid systems. Taking the experimental delta G values and computed component free energy terms for a set of duplexes, we set up multiple regression equations to predict their stabilities. After back-check and validity tests, we apply this model to predict delta G values for a large number of duplexes and two tRNA molecules (tRNAphe and tRNAasp). There is excellent agreement between the theoretical predictions and experimental observations. The considered duplexes with four to 16 base-pairs and the tRNA molecules have delta G values in a narrow range, 5-20 kcal mol-1, a range seen in a variety of globular proteins. There is no relationship between delta G and N, the number of nucleotides in the molecule. Base-stacking, hydrogen bonding and van der Waals factors contribute significantly, whereas hydrophobic and electrostatic factors contribute, respectively, marginally and minimally. The major factor which gives sequence specificity is base-stacking. The new set of atomic solvation parameters (ASPs) derived to estimate hydrophobic free energy brings to light the dangers of using already available ASPs, which emphasize the role of the hydrophobic factor unrealistically.