Best route from Murphy, NC to Knoxsville, TN

With a large RV, I'd avoid US74 WEST to I75, which will run you through the Ocoee River Valley. Pretty drive, but if you want to avoid tight turns it's not the route I'd pick. While it would be around an hour longer, I'd consider taking US74 EAST from Murphy, through Bryson City and picking up I-40 to head west to Knoxville. Other than a fairly short stretch through the Nantahala, it's primarily 4 laned and not very twisty.