This is a game of epic action and hi-octane thrills that is more suited to games like Scion or high level D&D and Pathfinder. Games like World of Darkness's monster races (for example Vampires, Geists, and Werewolves) would also work well if you give them a lot of experience points and epic attributes (9 / 7 / 5 for attributes and 17 / 14 / 9 for skills with about 20 merit points). It is not such a good idea if you're using systems like BRP which just don't quite capture that powerful combat feel.
This is a gory and violent game so remember to keep combat descriptions fast and visceral. Bones break, blood spurts, and organs are crushed. Don't describe the players characters in pain as they are far too epic (or inhuman) to feel it but do describe their enemies screaming or reeling in pain and horror because the player characters are just that powerful.
On that note, the enemy should be eeevil. As in, take the worst of Nazi Germany's principles, blend with the worst instances of scientific abuse, adds some drops of serial killer mentality, and allow to simmer. The player characters should never doubt that the bad guys are so bad that civilian casualties pale in comparison to letting the enemy exist. Oh, and never characterise any civilian who randomly gets killed.
Civilians should be hard to empathise with. They should run around like ants in confusion, screaming and waving their arms about in terror. If you do characterise them, bear in mind that you're drifting into Action Horror territory which may lead some players to restrain their characters and play them as anti-heroes rather than have to cope with the guilt of slaying realistic humans. You can go this way, it even lines up somewhat with the feel from Prototype 2, but it certainly moves the game further away from the spirit of the first where you're an evil badass up against people who are all the more evil.
Encourage imagination. It shouldn't be about what the rules specifically state you can do but rather what the players have come up with. So long as it's vaguely within the bounds of what their stats support, let them do it. Either that or give them a ton of merits or feats to ensure that if they want to swing off a balcony and decapitate someone, they can.
Also remember that this is meant to be a free roaming game. There should be a sense of the epic that encompasses the setting as well. This is the sort of game that really needs the players to be able to check out an entire big city as well as one that gives them a lot of really interesting places to sneak around in. Aircraft hangars, government institutions, mega-corporation headquarters, security bases, police stations, if its a place that the players would never be able to get into than its precisely the sort of place the characters should have no trouble exploring.
To this end, some form of shape shifting is a boon because a game of epic action will lead to their faces plastered all over wanted posters or televisions about the city and there won't be any downtime or peace in this game unless they can pretend to be somebody else.
Speaking of increased police attention, it is a good idea to figure out how you might escalate the danger. In Prototype, you would fight lone soldiers, groups of soldiers, tanks, and aircraft (alongside the escalating mutant threat). In a fantasy game, you could perhaps have it range from soldiers to undead soldiers on monstrous mounts to dragons whom you can control if you manage to knock off the rider. Either way, there should be a sense of escalating threat every time they run around being epic for too long which both warns AGAINST being too epic and is a reward FOR being that epic. Therefore, such escalations shouldn't lead to instant death but simply complicate matters if they're in the middle of a quest.
Man, that's how I feel on Mondays....
Prototype is very much a game of having the right key for every lock. In this case, those keys are scything blades, shields, and massive bludgeoning strikes. While everyone may have their preference and their favored combinations, there are still times when you have to use a particular ability.
While I wouldn't go so far as to suggest immunity to all but one of each characters' attacks, you can work in certain situations that benefit particular skills. In Pathfinder, you could give an enemy massive damage resistance that can only be bypassed by bludgeoning, slashing, piercing, or elemental attacks (fire, cold, electricity) although that still doesn't help encourage certain attacks simply because most characters don't have access to each type of swing.
While World of Darkness and other systems aren't set up for this, you could invent a sort of Damage Resistance trait whereby damage is reduced by a certain amount unless a certain type of attack is used.
Another option is to give them feats or merits that only come into play with certain attacks. Perhaps their defense goes up unless they use fire or perhaps the enemy will always choose to use a Sunder attack in response to the wrong type of strike. Again, though, this can get clumsy, especially if you don't find some way of letting the players know which one of their attacks would bypass that issue. They may not think of trying a trial and error approach and, even if they did try it, there's no reason why they'd figure out the right approach in any one combat. Still, you could make it work depending on your players and the manner in which you give them the required information.
A campaign based around Prototype, or including elements of it, should appeal to Action Heroes who will enjoy being epic, stretching their powerful muscles, and engaging in high octane battles across the city. Explorers will enjoy being able to get into everything and anything, as well as exploring the powers themselves, and Tacticians will figure out how to use their powers to their best advantage in every situation. Be cautious of letting things get too easy for them as Tacticians like a challenge.
This game isn't as much one for Communicators who will want to explore the psychological and social repercussions of being a creature with so much power and will therefore keep tilting the game in a very different - albeit valid - way. Depending on your group composition, you may have to either accept that tilt or work with them so that they occasionally get to explore those deeper philosophical questions while reminding them that this is generally just a chance to be epic. Investigators will want a mystery so ensure there's the odd conspiracy here and there to keep them engaged. The high octane combats are less likely to thrill them so ensure there are always juicy hints at the end of the combat rainbow so that they will stay motivated. If answers are just around the corner, they may well be quite eager to kick down the walls to reach it.
If you'd like to take a look at the trailer to learn more about this game, you can check it out here. If you'd like to read the sort of tropes that Prototype used, you can find them here.
For the next Game Translation, you have a choice of these: Left for Dead, The Sims 3, Half Life 2, Skyrim, The Last Express, Gears of War, Mass Effect, Dracula: Origins, Realms of the Haunting, Dragon Age 2, and pretty much any survival horror or horror game. If no one picks anything by next week, it'll be Skyrim.
If you want to see the list of games I've done thus far, you can find the Game Translation series starter over here.