Biophysical Society Conference | Tahoe 2023

Proton Reactions: From Basic Science to Biomedical Applications

Tuesday Speaker Abstracts

MOLECULAR DYNAMICS SIMULATIONS OF A VESICULAR GLUTAMATE TRANSPORTER IN DIFFERENT PROTONATION STATES Daniel Kortzak ; 1 Forschungszentrum Jülich, Jülich, Germany Neurons communicate via chemical synapses, which transmit signals from pre- to postsynaptic cells via neurotransmitter release into the synaptic cleft and subsequent binding to postsynaptic receptors. Presynaptic nerve terminals release neurotransmitters by exocytosis of synaptic vesicles, which have accumulated neurotransmitters suc h as monoamines, acetylcholine, γ aminobutyric acid (GABA), and glutamate with the help of specific vesicular neurotransmitter transporters (VNTs). The major excitatory neurotransmitter glutamate is accumulated by vesicular glutamate transporters (VGLUTs) in synaptic vesicles. where they also function as a major Cl - efflux pathway. Both glutamate transport and Cl - conductante are allostericaly activated by protons. Finding the proton acceptors or proton binding pathways is challenging because of the large number of titratable residues. Furthermore, mutagenesis experiments failed to identify residues important for protonation. Here we study the effect of different protonation states on the protein conformation and hydrogen bond networks within the protein. We found a large network spanning the whole membrane normal and connecting different protein domains. This large and flexible network with many redundancies could explain how VGLUT function is robust against many side-chain substitutions. INSIGHTS INTO THE QUANTITATIVE MECHANISM OF ION SELECTIVITY OF THE HUMAN VOLTAGE-GATED PROTON CHANNEL HV1 Yu Liu 1 ; Chenghan Li 2 ; Gregory A Voth 1 ; 1 The University of Chicago, Department of Chemistry, Chicago, IL, USA 2 California Institute of Technology, Division of Chemistry and Chemical Engineering, Pasadena, CA, USA Human voltage-gated proton (hHv1) channels are remarkable in their ability to selectively transport protons despite the substantial concentration difference between protons and other ions under physiological conditions. In spite of extensive experimental and computational investigations, the precise mechanism underlying proton selectivity remains elusive and subject to debate. I will present a quantitative explanation for the proton selectivity derived from our multi-scale simulations, combined with extensive free energy sampling. Our findings validate the pivotal role of Asp112, a pore-lining residue believed to be part of the selectivity filter, and we unveil a selectivity mechanism that may defy conventional expectations for ion transport rates -- protons permeate through Asp112 at rates only comparable to other ions. Interestingly, the proton selectivity is achieved through the strong proton affinity of the channel, and we demonstrate that Asp112, along with other protonatable residues, effectively enhances the proton concentration by six orders of magnitude, thereby enabling the channel to overcome the large concentration gap and selectively transport protons.

31