USR 250 through eastern OH and W. Va. is a very good route if you're looking to go two lanes. Many of my mates just hop on it and go until days end and then just turn around and come back. You say you want to be near the Smokies. If you're talking about the Park itself your a pretty good little hump in W. Va. / Va. Western N. C. will put you in closer proximity to the park and IMHO it's among the best areas for riding in the east.
Our route to the BR Parkway is typically IR 77 (W. Va. pike) which is very scenic for an interstate. Often spend the night in Fancy Gap, Va. at the intersection of the BRP and I-77. The area around Hawk's Nest State Park and the New River gorge are excellent riding.
Agree that Rt 250 is a great ride, although I haven't been on it in years. From what I recall, take advantage of gas stations when you see them. Also, the New River Gorge area had some great roads to experience. The last time I was down there, I stayed in a hotel a few miles north of New River Gorge that had an indoor pool and jacuzzi, and easy on the wallet. Great way to relax after a long day of riding. They had good food in the adjoining parking lots and also adjoined Walmart's parking lot. What else could you need...a jacuzzi, good food, and Walmart? I would say that you are probably looking at more than 350 to get there from Indy though. I happened upon a route that took us about 150 miles through nothing but gorgeous scenery, not a stop light to be found along the way, and the only real signs of life were gas stations about every 9 to 10 miles. The final leg of that ride took us up and down Galley Mountain, just before New River Gorge, and that was an unbelievable ride. Up and down incredible twistys with waterfalls along the sides of the road. I want to take that ride again someday soon.