We critically examine a recently proposed convective replica exchange (cRE) method for enhanced sampling of protein conformation based on theoretical and numerical analysis. The results demonstrate that cRE and related replica exchange with guided annealing (RE-GA) schemes lead to unbalanced exchange attempt probabilities and break detailed balance whenever the system undergoes slow conformational transitions (relative to the temperature diffusion timescale). Nonetheless, numerical simulations suggest that approximate canonical ensembles can be generated for systems with small conformational transition barriers. This suggests that RE-GA maybe suitable for simulating intrinsically disordered proteins, an important class of newly recognized functional proteins. The efficacy of RE-GA is demonstrated by calculating the conformational ensembles of intrinsically disordered kinase inducible domain protein. The results show that RE-GA helps the protein to escape nonspecific compact states more efficiently and provides several fold speedups in generating converged and largely correct ensembles compared to the standard temperature RE. © 2014 Wiley Periodicals, Inc.