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Energy landscape along an enzymatic reaction trajectory: hinges or cracks?

ABSTRACT: Are the most dynamically flexible regions around the equilibrium structure of an enzyme the same regions involved in the transition state for rate limiting processes involved in the enzymatic reaction? Kern and-coworkers (Wolf-Watzet al., 2004; Henzler-Wildman et al., 2007a, 2007b) have shown that insights about functionally relevant motions that determine the overall enzyme turnover rate can be obtained by investigating conformational dynamics around the equilibrium basin of the enzyme adenylate kinase. An allosteric change in protein structure turns out to be the controlling process. In this commentary we compare results of this study with earlier predictions of the route by which the enzyme undergoes its conformational change. These predictions are based on the idea that the energy surface for the protein is determined by the end structures of the conformational change. A key issue is whether the protein moves by specific hinges or whether it "cracks" and accesses partially unfolded states during its structural change.

SUBMITTER: Whitford PC

PROVIDER: S-EPMC2645576 | biostudies-other | 2008 Apr

REPOSITORIES: biostudies-other

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Project description:The calculations of potential of mean force along complex chemical reactions or rare events pathways are of great interest because of their importance for many areas in chemistry, molecular biology, and material science. The major difficulty for free energy calculations comes from the great computational cost for adequate sampling of the system in high-energy regions, especially close to the reaction transition state. Here, we present a method, called FEG-RBD, in which the free energy gradients were obtained from rigid body dynamics simulations. Then the free energy gradients were integrated along a reference reaction pathway to calculate free energy profiles. In a given system, the reaction coordinates defining a subset of atoms (e.g., a solute, or the quantum mechanics (QM) region of a quantum mechanics/molecular mechanics simulation) are selected to form a rigid body during the simulation. The first-order derivatives (gradients) of the free energy with respect to the reaction coordinates are obtained through the integration of constraint forces within the rigid body. Each structure along the reference reaction path is separately subjected to such a rigid body simulation. The individual free energy gradients are integrated along the reference pathway to obtain the free energy profile. Test cases provided demonstrate both the strengths and weaknesses of the FEG-RBD method. The most significant benefit of this method comes from the fast convergence rate of the free energy gradient using rigid-body constraints instead of restraints. A correction to the free energy due to approximate relaxation of the rigid-body constraint is estimated and discussed. A comparison with umbrella sampling using a simple test case revealed the improved sampling efficiency of FEG-RBD by a factor of 4 on average. The enhanced efficiency makes this method effective for calculating the free energy of complex chemical reactions when the reaction coordinate can be unambiguously defined by a small subset of atoms within the system.

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Energy landscape along an enzymatic reaction trajectory: hinges or cracks?

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