Calculation of pathways for the conformational transition between the GTP‐ and GDP‐bound states of the Ha‐ ras ‐p21 protein: Calculations with explicit solvent simulations and comparison with calculations in vacuum

The transitions between the water‐equilibrated structures of the GTP and GDP forms of Ha‐ ras ‐p21 have been calculated by using the targeted molecular dynamics (TMD) method (Schlitter et al., Mol. Sim. 10:291–309, 1993) both in vacuo and with explicit solvent simulation. These constrained molecular dynamics calculations result in different pathways, depending on the nucleotide bound. Each pathway consists in a sequence of transitions affecting six segments of the protein, four of them forming a hydrophilic cleft around the nucleotide. The transitions are initiated by the removal or introduction of the γ‐phosphate of the nucleotide and proceed sequentially, crossing several low‐energy transition states. The movements are transmitted either by direct interactions between the segments or through the nucleotide. The GTP to GDP pathway is initiated by the removal of the nucleotide γ‐phosphate. This gives some space to Gly12, Gly13, and Val14. Their movement is transmitted to the target recognition domain and the switch II region, forcing these segments to adopt another position. In a second step the target recognition domain and the switch II region undergo conformational transitions to reach an intermediate conformation. Finally, there is a relaxation of the target recognition domain to its final state that forces the switch II region to reach its target conformation. The calculated pathways allow the identification of many residues that play an important role in the conformational changes, explain the altered transformation properties of some, and suggest mutations to alter the pathway. Proteins 28:434–451, 1997. © 1997 Wiley‐Liss, Inc.