title: Toward Determining ATPase Mechanism in ABC Transporters: Development of the Reaction Path-Force Matching QM/MM Method.
abstract: Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are ubiquitous ATP-dependent membrane proteins involved in translocations of a wide variety of substrates across cellular membranes. To understand the chemomechanical coupling mechanism as well as functional asymmetry in these systems, a quantitative description of how ABC transporters hydrolyze ATP is needed. Complementary to experimental approaches, computer simulations based on combined quantum mechanical and molecular mechanical (QM/MM) potentials have provided new insights into the catalytic mechanism in ABC transporters. Quantitatively reliable determination of the free energy requirement for enzymatic ATP hydrolysis, however, requires substantial statistical sampling on QM/MM potential. A case study shows that brute force sampling of ab initio QM/MM (AI/MM) potential energy surfaces is computationally impractical for enzyme simulations of ABC transporters. On the other hand, existing semiempirical QM/MM (SE/MM) methods, although affordable for free energy sampling, are unreliable for studying ATP hydrolysis. To close this gap, a multiscale QM/MM approach named reaction path-force matching (RP-FM) has been developed. In RP-FM, specific reaction parameters for a selected SE method are optimized against AI reference data along reaction paths by employing the force matching technique. The feasibility of the method is demonstrated for a proton transfer reaction in the gas phase and in solution. The RP-FM method may offer a general tool for simulating complex enzyme systems such as ABC transporters.
authors: Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States.
authors: Y
authors: Y
authors: Zhou
authors: Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States.
authors: P
authors: P
authors: Ojeda-May
authors: Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States.
authors: M
authors: M
authors: Nagaraju
authors: Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States. Electronic address: jpu@iupui.edu.
authors: J
authors: J
authors: Pu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D006801:Humans; D006868:Hydrolysis; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate
keywords: ABC transporter; ATP hydrolysis; Enzyme mechanism; Force matching; Free energy simulation; Multiscale simulation; Proton transfer; QM/MM; Reaction path; Specific reaction parameter