  Protein function frequently involves conformational changes with large
amplitude on timescales which are difficult and computationally expensive to
access using molecular dynamics. In this paper, we report on the combination of
three computationally inexpensive simulation methods-normal mode analysis using
the elastic network model, rigidity analysis using the pebble game algorithm,
and geometric simulation of protein motion-to explore conformational change
along normal mode eigenvectors. Using a combination of ELNEMO and FIRST/FRODA
software, large-amplitude motions in proteins with hundreds or thousands of
residues can be rapidly explored within minutes using desktop computing
resources. We apply the method to a representative set of six proteins covering
a range of sizes and structural characteristics and show that the method
identifies specific types of motion in each case and determines their amplitude
limits.
