Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport

Abstract

Ion translocation across biological barriers is a fundamental requirement for life. In many cases, controlling this process-for example with neuroactive drugs-demands an understanding of rapid and reversible structural changes in membrane-embedded proteins, including ion channels and transporters. Classical approaches to electrophysiology and structural biology have provided valuable insights into several such proteins over macroscopic, often discontinuous scales of space and time. Integrating these observations into meaningful mechanistic models now relies increasingly on computational methods, particularly molecular dynamics simulations, while surfacing important challenges in data management and conceptual alignment. Here, we seek to provide contemporary context, concrete examples, and a look to the future for bridging disciplinary gaps in biological ion transport. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain.

In Silico Electrophysiology of Inner-Ear Mechanotransduction Channel TMC1 Models

“…To investigate TMC1 conduction properties we performed simulations in which transmembrane potentials of -0.500 V (Sim1c) and -0.250 V (Sim1d) were applied using an external electric field 87,88 (Tables 1 and 2). These transmembrane potentials are large compared to physiological values (up to -0.125 V) 89 , but allowed us to explore conduction events on short simulation timescales, as routinely done in MD simulations of ion channel systems 87,88,[90][91][92][93][94] . To determine whether helices α4 and α6 would influence conductance, we chose a TMC1 conformation in which the Met 418 -Thr 535 distance was large for monomer A and small for monomer B, obtained after 60 ns of equilibration for the full-length model 1 (Fig.…”

The Structural Basis of IKs Ion-Channel Activation: Mechanistic Insights from Molecular Simulations

“…Because single-channel dynamics are stochastic, extensive IKs structural changes occur between closed and open states as a function of Vm and time, ensuing in multiple transition pathways over a millisecond-to-second timescale. Therefore, multiple endpoints molecular dynamics computations are not viable on a physiological timescale (5, 29). Previous structure-based functional models did not account for SCs because a single-conductance concerted or allosteric constraint was assumed to simulate current (12, 13, 14, 15).…”

The Structural Basis of IKs Ion-Channel Activation: Mechanistic Insights from Molecular Simulations

“…Since single-channel dynamics are stochastic, extensive IKs structural changes occur between closed and open states as a function of V m and time, ensuing in multiple transition pathways over millisecond-to-second timescale. Therefore, multiple endpoints MD computations are not viable on a physiological timescale (5,29). Previous structure-based functional models did not account for subconductances because a concerted or an allosteric constraint was assumed in order to simulate current (12)(13)(14)(15).…”