Sampling protein conformations and pathways

Protein flexibility and rigidity can be analyzed using constraint theory, which views proteins as 3D networks of constraints involving covalent bonds and also including hydrophobic interactions and hydrogen bonds. This article describes an algorithm, ROCK (Rigidity Optimized Conformational Kinetics), which generates new conformations for these complex networks with many interlocked rings while maintaining the constraints. These new conformations are tracked for the flexible regions of a protein, while leaving the rigid regions undisturbed. An application to HIV protease demonstrates how large the flap motion can be. The algorithm is also used to generate conformational pathways between two distinct protein conformations. As an example, directed trajectories between the closed and the occluded conformations of the protein dihydrofolate reductase are determined.