A Second Look at Canonical Sampling of Biomolecules using Replica   Exchange Simulation
  Because of growing interest in temperature-based sampling methods like replica exchange, this note aims to make some observations and raise some potentially important questions which we have not seen addressed sufficiently in the literature. Mainly, we wish to call attention to limits on the maximum speed-up to be expected from temperature-based methods, and also note the need for careful quantification of sampling efficiency. Because potentially lengthy studies may be necessary to address these issues, we felt it would be useful to bring them to the attention of the broader community. Here \emph{we are strictly concerned with canonical sampling at a fixed temperature,} and \emph{not} with conformational search. 
Daniel M. Zuckerman and Edward Lyman