A new method to detect remote relationships between protein sequences and known three‐dimensional structures based on direct energy calculations and without reliance on statistics has been developed. The likelihood of a residue to occupy a given position on the structural template was represented by an estimate of the stabilization free energy made after explicit prediction of the substituted side chain conformation. The profile matrix derived from these energy values and modified by increasing the residue self‐exchange values successfully predicted compatibility of heatshock protein and globin sequences with the three‐dimensional structures of actin and phycocyanin, respectively, from a full protein sequence databank search. The high sensitivity of the method makes it a unique tool for predicting the three‐dimensional fold for the rapidly growing number of protein sequences. © 1994 Wiley‐Liss, Inc.