What I'd recommend is just using one of the normal search engines (Travelocity, Opodo or - my flawed favourite - the
ITA Software demo) to get an idea of what the fares would be like doing it as one ticket.
Then price some straight returns to your gateway(s) - open jaw if necessary - to see what the differential is.
If the multi-leg itinerary is significantly more expensive, as it often is, then I'd recommend buying the trans-Atlantics separately from the US domestics. You'll then have the freedom to choose your airlines, routes, service levels (
) and prices for all the domestic legs. This will allow you to use some of the low-fare domestics in the US, if appropriate, whose service levels are now paradoxically often higher than the major airlines'.
Things to watch out for in the ITA Software demo are:-
(a) you must put a UK city (LON will do) for the sales point, to get SITI fares which are usually the best for ex-UK international tix;
(b) it doesn't display all airlines - I think that US is one of the notable absent members for trans-Atlantics;
(c) its tax calculations are hopeless, so use the base fares as comparisons;
(d) in the detailed price breakdowns, base fares are usually shown in NUC (which is I think in effect the same as USD), so you will need to do a currency conversion to get the GBP base price.
SITI = Sold Inside [country of origin], Ticketed Inside
NUC = Notional Units of Calculation/Construction