Final answer:
The Southern colonists interacted most extensively with the Cherokee, particularly during conflicts like the Tuscarora and Yamasee Wars and the American Revolutionary War.
Step-by-step explanation:
The Southern colonists had the most interaction with the Cherokee Native American group. During various conflicts and wars, the Cherokee frequently engaged with the colonists, either as allies or foes. In the Tuscarora War, the Cherokee supported the colonists against their enemies, the Creek who sided with the Yamasee. Their involvement was significant during the Yamasee War, tipping the scale in favor of the colonists. Furthermore, the Cherokee's interactions during the American Revolutionary War were complex, with individuals rallying against the colonials while others sought neutrality.