Camshaft has ALOT to do with the entire performance and fuel economy successes or failures of an engine. It's also about where in the rpm range the engine makes the numbers vs the rpm where the cruise speeds are at. Once again, that is another area where camshaft will make you or break you. Fuel vaporization is also an INSANELY huge factor in both the performance and mileage successes or failures an engine. If the system does a poor job of fuel vaporization, it will waste alot of gas.
This is an area where a spread bore carburetor will reign superior over a square bore. Airflow is pointless without great vaporization characteristics, as air does not burn without fuel vapor.
Don't over pipe the exhaust system in terms of diameter.
Don't be the least bit afraid of a 289/302 as a baseline. Be afraid of the wrong combination.