Extending the stochastic titration CpHMD to the AMBER14SB force field for future search of non-opioid analgesics

João G. N. Sequeira^1,2, Adrian E. Roitberg², Miguel Machuqueiro¹

1 - BioISI: Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
2 - Department of Chemistry, University of Florida, Gainesville 32603, USA

Acid-sensing ion channels (ASICs) are voltage-insensitive, proton-gated cation channels, widely expressed throughout the central and peripheral nervous system, that are involved in diverse physiological processes ranging from nociception to brain ischemia [1]. ASICs are activated by extracellular acidosis and ligands can act as antagonists or agonists for the channel’s affinity for protons [2]. To discover ASIC activity modulators, it is crucial to understand the pH effects on the conformational rearrangement of the protein channel that leads to a change in the cation membrane permeability.

Constant-pH Molecular Dynamics (CpHMD) methods are pivotal to describe pH and its effects on the conformational space of biological systems [3]. The stochastic titration CpHMD (st-CpHMD) method has shown excellent performance over the years [3,4]. Until recently, our implementation of this method only supported the GROMOS 54A7 [3] and the CHARMM36m force fields [4]. We are currently working on the extension of this method to support the AMBER 14SB force field, an all-atom force field that is particularly suited for disordered proteins and nucleic acids. However, since the charge parameterization procedure of this force field allows side chain charge propagation to the main chain, we propose a small modification to the official ff14SB atomic partial charges to make them st-CpHMD-compatible. Here, we will present our preliminary results using this protocol.

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