Protein–nucleic acid interactions — Which amino acids most commonly engage the DNA/RNA phosphate backbone via electrostatic attraction?

Introduction:
Phosphate groups on nucleic acids are negatively charged. Proteins use basic side chains to contact this backbone and stabilize complexes. This question asks which residues most typically make those interactions.

Given Data / Assumptions:

• DNA and RNA backbones are rich in negatively charged phosphates.
• Electrostatics guide initial association in many complexes.
• Side chain chemistry determines interaction preferences.

Concept / Approach:
Lysine (ε-amino) and arginine (guanidinium) are positively charged at physiological pH. Their long, flexible side chains form strong ionic and hydrogen bond contacts with phosphate oxygens, explaining their enrichment at nucleic acid binding interfaces.

Step-by-Step Solution:

Verification / Alternative check:
Sequence logos and structural analyses of DNA binding domains (e.g., helix–turn–helix, zinc fingers) show overrepresentation of Lys/Arg facing the backbone.

Why Other Options Are Wrong:

• Ile/Val and Leu/Ala: nonpolar; prefer hydrophobic cores rather than anionic phosphate contact.
• Cys/Met: can coordinate metals or form disulfides (Cys) but are not typically used for phosphate neutralization.
• Phe/Trp: aromatic and hydrophobic; may stack with bases but not primarily backbone contacts.

Common Pitfalls:
Confusing base-stacking or base-specific contacts with backbone neutralization; the latter is mainly the role of basic residues.

Final Answer:
Lys and Arg.