(304f) How CO2 Diffuses into the Active Site of Carbonic Anhydrase: A Study By Molecular Dynamics Simulation and Multi-Scale Markov-State Modeling

Chen, G., Tsinghua University
Lu, D., Key Lab of Industrial Biocatalysis, Ministry of Education, Tsinghua University
Wu, J., University of California Riverside
Liu, Z., Key Lab of Industrial Biocatalysis, Ministry of Education, Tsinghua University
While a significantly enhanced capture of CO2 has been accomplished with the aid of carbonic anhydrase (CA), which catalyzes the conversion of CO2 to bicarbonate at an extremely fast rate, the molecular mechanism for the diffusion of CO2 from the bulk aqueous phase into the active site of CA is not yet established. Here, we present theoretical results from molecular dynamics (MD) simulation and multi-scale Markov-state modeling (MSM) of the CO2 diffusion process using carbonic anhydrase (α-human CA II, EC as a model enzyme. CO2 diffusion along the natural gateway of CA was illustrated with a two-dimensional free energy landscape along two reaction coordinates, i.e., the CO2 distance (center of mass) from a water molecule attached to the zinc complex, and the orientation angle formed by OH2O-CCO2-OCO2 atoms. Two distinct diffusion modes were identified using the Perron cluster cluster analysis (PCCA) in combination withthe flux analysis for the transition rate matrix of the coarse-grained Markov state model (CG-MSM). The simulation results for Km, one key parameter of the Michaelis-Menten equation, agreed well with that from the experimental data. Moreover, the multi-scale MSM indicated a preferential accumulation of CO2 at the hydrophobic pockets inside CA. A good understanding of the molecular events underpinning enzyme kinetics will be helpful for both molecular re-engineering of CA by either chemical or genetic methods as well as for process intensification or renovation for CA-assisted CO2 capture and utilization.