One of the serious challenges is to develop a methodology for accurately estimating the configurational entropy of macromolecules. We propose an effective scheme by using a variable transformation approach in combination with the independent component analysis concept. The validity of the new approach is demonstrated by presenting results of alanine and beta-hairpin peptides in aqueous solution. It is shown that the new method is very fast, simple but yields estimates of the entropy which are much closer to the exact entropy than previously available techniques. (C) 2008 Elsevier B. V. All rights reserved.