Biophysical Society Conference | Tahoe 2023

Proton Reactions: From Basic Science to Biomedical Applications

Poster Abstracts

8-POS Board 8 CONSTANT PH MOLECULAR DYNAMICS SIMULATIONS OF THE ANION EXCHANGER-1 (AE1) Balarama Sridhar Dwadasi 1 ; Hristina Zhekova 1 ; Sergei Y Noskov 1 ; D. Peter Tieleman 1 ; 1 University Of Calgary, Department of Biological Sciences, Centre for Molecular Simulation, Calgary, AB, Canada The Solute Carrier 4 (SLC4) family of transporters perform an important function of maintaining the acid-base homeostasis in the body. In particular, the Anion Exchanger 1 (AE1) is involved in the exchange of chloride/bicarbonate ions in the erythrocytes and kidneys. The binding pockets and ion permeation pathways of AE1 contain several titratable residues which may play an important role in the transport of ions. Experimental evidence suggests that E681, an acidic residue in the central binding site S1 of the AE1 pocket, when protonated facilitates the transport of divalent anions (1). The acid-base equilibrium of bicarbonate/carbonate further complicates this scenario. Molecular dynamics simulations conducted by our group in prior studies revealed that protonation of E681 impacts the frequency and longevity of ion binding events at site S1 (2). However, these methods are limited by assignment of discrete protonation states throughout the simulation, which do not change in response to potentially important environmental effects. Protonation states are affected by environmental factors such as pH, ionic strength, and nearby amino acids. Constant pH Molecular Dynamics (CpHMD) techniques simulate dynamic protonation events in molecular systems and we adopt them in the present study for assessment of the protonation states of residues of importance in the binding pocket of AE1. We will present the pKa values of the key titratable residues of the transporter and the bicarbonate anion. References 1. Jennings, M. L. (2021) Cell physiology and molecular mechanism of anion transport by erythrocyte band 3/AE1. Am. J. Physiol. Physiol. 321, C1028–C1059 2. Zhekova, H. R., Pushkin, A., K ayık, G., Kao, L., Azimov, R., Abuladze, N., Kurtz, D., Damergi, M., Noskov, S. Y., and Kurtz, I. (2021) Identification of multiple substrate binding sites in SLC4 transporters in the outward-facing conformation: Insights into the transport mechanism. J. Biol. Chem. 296, 100724

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