Constant pH Molecular Dynamics Simulations of Nucleic Acids in Explicit Solvent

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• Nucleosides adenine and cytosine typically have low pKa values, suggesting they are unprotonated at physiological pH.
• Recent studies indicate protonated forms of adenine and cytosine are prevalent in RNA macromolecules.
• Protonated nucleotides may influence RNA stability and ribozyme catalytic mechanisms.

Purpose of the Study:

• To establish a framework for constant pH molecular dynamics simulations (CPHMD) for nucleic acids.
• To investigate the coupled dynamics of protonation states and RNA structure using CPHMD.
• To validate the accuracy of CPHMD by comparing calculated pKa values with experimental data.

Main Methods:

• Development and application of constant pH molecular dynamics simulations (CPHMD) for RNA.
• Utilizing a novel functional form, λ(Nexp), for Multi-Site λ-Dynamics (MSλD).
• Simulating nucleic acids in explicit solvent, coupling protonation state to RNA dynamics via λ-dynamics.

Main Results:

• CPHMD achieved good sampling, enabling rapid transitions between protonated and unprotonated nucleotide states at pH = pKa.
• Calculated pKa values for simple nucleotides showed strong agreement with experimental measurements (mean absolute error of 0.24 pKa units).
• Demonstrated the capability of CPHMD to accurately model pH-dependent behavior in nucleic acids.

Conclusions:

• CPHMD is a powerful computational tool for studying pH-dependent properties of RNA.
• The study provides a new method to explore the role of nucleotide protonation in RNA structure and function.
• Findings contribute to understanding the molecular mechanisms underlying RNA's biological roles.