Despite being a pilot in real life, I tend to skip out on doing much fuel/payload calculations in FSX with the exception of airliners and the odd jet.
You would need at least two things in FSX for realistic calculations: First you need a pilot handbook of some sort that lists figures such as the fuel for taxi, the fuel burn rate at specific pressure altitudes and temperatures, amount of fuel and time burnt off during climbs (and descents sometimes), figures that describe the maximum gross weights (max weight you can have) and your C of G limits (the limits where the aircraft becomes too nose or tail heavy).
The second thing you need is an FSX model that reflects accurately to the manuals. The figures are useless if the flight modelling is way off. Its much easier to take the nav log amount and add a percentage to that instead. There are payware aircraft, however, that do fly close to the real numbers, so that is always something to look into.
A final thing you might consider is legal requirements pertinent to whatever virtual country your flying at. Here in Canada, for instance, we are required to carry 30 minutes of reserve based on cruise for a day VFR flight (45 at night). There is also a requirement for IFR to carry extra for flying to a single alternate and also an overshoot.
This becomes a little bit cumbersome and time consuming in flight simming. In addition to the stated requirements above, there are also factors like forecasted winds that one must take into account when calculating fuel and such. You almost need a flight computer (google up like an E6B computer) to do these crazy calculations.
Fuel calculations in general are... not hard... but a little tricky if you want to do it like in real life. Most light aircraft would generally carry more than they need (i.e., full tanks even for a short run), so its not much of a factor unless your flying to a destination that cuts into reserves (extra fuel). Medium jets to heavy jets are a different story, for most of the time, they carry what they need. Myself, in the sim, I just factor in a percentage or a few thousand pounds extra in such cases

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Calculating fuel and payload will probably take 10 pages worth of text to explain, so instead of doing that, I'll just give you a few simming rules of thumb that while, won't be totally realistic, shouldn't be too far off:
1) Know the maximum gross weight (or take-off weight) of your aircraft. Look in the learning center, or any documents that come with it. Google up a pilot operating handbook (POH), and you can get figures on maximum weight and such. These are figures that indicate the max amount of weight you can throw on the aircraft, and realistically, you don't want to go over that.
2) Know the C of G (center of gravity) limits of your aircraft, which is again found in POHs, documents, or what nots. A forward C of G means your nose heavy. An aft C of G means your tail heavy. You don't want your aircraft to be over the limits on either end of the spectrum.
3) In general, the higher you go, the less fuel you burn. If your flying a piston engine aircraft (i.e., Cessna 172), don't forget to lean your mixture the higher you go up. You burn less fuel that way and your engine doesn't run as rough. If your flying a jet aircraft, you probably want to pull your throttles down a notch while at cruise
4) A headwind will force you to burn more fuel. You will burn less in a tailwind. With headwinds, your aircraft won't move as fast over the ground, and hence it would take more time to reach your destination!
5) You can find fuel computers for certain FSX aircraft on the internet that will do the dirty work of fuel calculations for you. You might want to search them up on avsim.com, flightsim.com, or just google them.
6) In real life, you have to do weight x arm = moment and total moment / weight = C of G type calculations. You don't really need to do that in FSX because the fuel and payload windows do the calculations for you (properly I hope). In any case, as stated in point one and two, don't go over gross weight and keep the C of G within limits and you should be good to go.