Technical Issues and Error Analysis

Of the three methods discussed above, FEP, TI, and slow growth, the first two see far more application than the third. The slow-growth condition, that the system is constantly at, or at least very, very near equilibrium, is quite hard to maintain over the course of a 

In formalism, many aspects of free-energy simulations lend themselves more to implementation within a Monte Carlo sampling scheme than within a molecular dynamics scheme. Unfortunately, MC schemes applied to large flexible molecules (e.g., proteins) tend to be very inefficient, since most proposed moves of the large molecule are rejected as being too energetically unreasonable, so MD simulations remain the standard. Innovative attempts to combine some of the best features of both have been described, as already noted in Chapter 3. 

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