Howdy
One thing to remember is the basic shape of a Ruger single action revolver grip goes back about 160 years to the Colt Navy revolver of 1851. There have been some minor changes along the way, but most Ruger single action grips mimic the Colt Single Action Army grip, which itself is the same as the old 1851 Navy grip.
Another thing to remember is that the old 1851 Navy grip was not really meant to have your entire hand crammed onto it. I'm reading between the lines here, but I'll bet you are trying to cram your entire hand onto the grip. I really don't think Wild Bill's hands were any smaller than ours are today. I'll bet you dollars to donuts, Wild Bill curled his pinky under the grip, I'll bet he did not try to cram his entire hand onto the grip.
Another thing to think about, is to forget everything your old DI taught you about keeping your grip as high as possible on the gun. These ain't semi-autos. With most semi-autos it is not physically possible to get your middle finger behind the trigger guard. With a single action revolver it is, and if you cram your entire hand onto the grip so that your middle finger is touching the trigger guard, when you start shooting some heavy recoiling loads your knuckle is going to get whacked by the trigger guard and it is going to hurt.
I ALWAYS curl my pinky under the grip of my single actions, Ruger, Colt, Uberti, S&W, what ever. Curling my pinky under the grip allows me to shift down on the grip. The key here is, rather than trying to hold as high as possible on the gun, by shifting down a bit I open up about 1/4" of space between the rear of the trigger guard and the knuckle of my middle finger. The 1/4" of space means the trigger guard never whacks my knuckle, no matter how heavy the load.
Lastly, don't try and hold it with a death grip. Allow the grip to rotate slightly in your hand with recoil. That's what it is supposed to do. That's why it has such a nice curve. When gun manufacturers started putting that hump on the grip behind the hammer, it was supposed to prevent the grip from rotating in your hand. Let the grip rotate. It will bring the hammer spur closer to your thumb and make it easier to cock the hammer for the next shot. It ain't gonna make much difference with a Single Six, but when you try shooting a Vaquero chambered for 45 Colt it will make a world of difference.
The Ruger Bisley grip is only an approximation of what the original Colt Bisley grip looked like. It is more straight up and down than the original, and it is longer. Those who like to cram their entire hand onto the grip like the longer Ruger Bisley grip, but you will still have your knuckle hard against the trigger guard and it will probably hurt if you try shooting heavy recoiling loads.
Try my suggestions and see if you like it a little bit better. I can shoot full power Black Powder 45 Colt loads our of a Colt, clone, or Ruger all day long and it is very comfortable.
Of course, I have been shooting single action revolvers for over 40 years, so that may have something to do with it.