I usually try about 4 or 5 different keys for each song but it's not my comfort level that I'm interested in. Too high can sound strained and too low will bore the listener.
When I'm not sure, I record it and listen.
As for the instrument... I have coal miner's fingers and never was trained in an instrument. I can pretty well play in any key but during a 3 or 4 hour gig will stick to playing in G, C. Dm & Am and capo up. I am better able to hear/feel the changes and thus able to concentrate more on my job.
There is absolutely no doubt though that the instruments sound far richer when unshackled.
As for the song... if singing is a way of enhancing the words then the more you can do to beautify the sound, the better. So I would say that choosing the right key for you and singing it as well as you can is the most important thing of all.
If the instrument of your choice is not well suited, there are always other instruments and other opportunities.