Effects of loop conformation on pKa and ligand binding in DNA gyrase B

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Abstract
Molecular dynamics simulations of the adenosine triphosphatase (ATPase) subdomain of DNA gyrase B were done to characterize the flexibility of two loops implicated in ligand binding. The simulations show that bound adenosine triphosphate (ATP) stabilizes the conformation of the two loops. Simulations of the ATPase subdomain without ATP show that the loops are more flexible and can assume alternative conformations. We further investigated the dependence of histidine pKa on the loop conformations using continuum dielectric calculations. Using multiple conformations, we showed that the protonation states of titratable groups in the flexible loops can depend on the loop conformation. This, in turn, will affect ligand binding and calculations such as the multiple copy simultaneous search (MCSS) method for small functional group binding. This illustrates the importance of accurately determining the protonation state of the protein prior to the calculation. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2004