Hydration Waters Make Up for the Missing Third Hydrogen Bond in the A·T Base Pair

Area of Science:

• Molecular Biology
• Biophysics
• Computational Chemistry

Background:

• Base pairing complementarity is fundamental to DNA structure and function.
• The differing number of hydrogen bonds between Guanine-Cytosine (G·C) and Adenine-Thymine (A·T) pairs is traditionally considered key to their specificity.
• Quantifying direct hydrogen bonds is challenging due to the influence of surrounding water molecules and distinct hydration structures around A·T and G·C pairs.

Purpose of the Study:

• To create a detailed map of the hydration structure around A·T and G·C base pairs in duplex DNA using large-scale computer simulations.
• To quantify the contribution of specific water molecules to the free energy of hydrogen bonds within these base pairs.
• To elucidate the role of hydration in determining the thermodynamic stability of A·T versus G·C pairs.

Main Methods:

• Employed large-scale computer simulations to model DNA duplexes.
• Developed a detailed map of hydration structures surrounding A·T and G·C base pairs.
• Utilized a thermodynamic construction based on equilibrium hydration fractions to quantify the free energy contributions of specific bound waters.

Main Results:

• Identified distinct hydration structures for A·T and G·C base pairs.
• Quantified the free energy contributions of specific hydration waters to individual hydrogen bonds.
• Demonstrated that minor groove hydration of A·T pairs can provide up to ~2 kcal/mol free energy, compensating for the missing third hydrogen bond compared to G·C pairs.

Conclusions:

• Hydration plays a critical role in stabilizing DNA base pairs, comparable to direct hydrogen bonding.
• The thermodynamic stability of A·T and G·C base pairs is rendered nearly equivalent due to the stabilizing effect of water molecules.
• This finding reframes the understanding of base pair specificity and DNA stability, highlighting the importance of the aqueous environment.