I don't know if there are penalties outside of lack of experience in the second or third position. But every player card has a "positions" tab that shows their potential at given positions. I've had a lot of success moving players that may have been drafted at CB and moving them to a Safety because that is where their highest potential lies. I have also had success in moving OL and DL to different positions within that group.
Someone who has done more experimentation and documentation may be able to answer more completely, but I think what it really comes down to is where their strengths are. Speed, acceleration, pass catching, etc. If they're a potential fit they can usually be at least serviceable at a variety of positions.
