Seminars2022 – 2026

Ligand-gated ion channels mediate chemical signaling throughout the nervous system. They function by selectively binding neurotransmitters in an extracellular domain, which leads to conformational changes that eventually open an ion conducting pore through the membrane, and numerous drugs such as anesthetics and alcohol modulate this process. We use a combination of cryo-electron microscopy and molecular simulations to determine the different conformational states in this process, and to understand selectivity as well as allosteric modulation. In particular, Markov State Models combined with thousands of microsecond-scale simulations enable us to model the full conformational landscape of the functional cycles occurring on millisecond timescales.

Prominent alkaloids derived from Mitragyna speciosa exhibit considerable potential for various pharmacological applications. Yet, their molecular interactions with cellular membranes remain poorly understood. In this study, molecular dynamics (MD) simulations were employed to investigate the behavior of three alkaloid compounds (mitragynine, 7-hydroxymitragynine and mitragynine pseudoindoxyl) with lipid bilayers. Several model systems comprising pure and/or mixed alkaloids were embedded in a fully hydrated dipalmitoylphosphatidylcholine (DPPC) lipid bilayer, and simulated using the GROMACS program for a duration of 100-200 ns. The simulation results show the alkaloids diffused into the lipid bilayer region in less than 50 ns duration. We observed the molecules preferentially position themselves beneath the lipid head groups. Hydrogen bonds were formed between alkaloids and the carbonyl and phosphate groups of the lipid bilayer, as well as water molecules from the aqueous region. These findings highlight the hydrophobic nature of the alkaloids, facilitating their integration into lipid bilayers. This study contributes valuable insights for the development of therapeutic strategies targeting membrane-associated processes.

Since its original development in 2006, CHARMM-GUI has proven to be an ideal web-based platform to interactively build complex molecular systems and prepare their simulation inputs with well-established and reproducible simulation protocols for state-of-the-art molecular simulations using widely used simulation packages. The CHARMM-GUI development project has been widely adopted for various purposes and now contains a number of different modules designed to set up a broad range of molecular simulation systems. Our philosophy in CHARMM-GUI development is less about providing the nuts and bolts of molecular modeling, but instead focused on helping users to achieve a task, such as building a membrane system or solvating a protein, by providing a streamlined interface. This design principle helps us to think of the workflow critically when designing the interface, which leads CHARMM-GUI to be accessible to users with little experience in modeling tools and remains useful to experts, especially for batch generation of systems. The CHARMM-GUI development project is still ongoing. CHARMM-GUI will continue to help expert and non-expert researchers from a broader range of the modeling and simulation community to build the complex molecular systems of their interest and prepare the input files for any general and advanced modeling and simulation through the large and unique scope of CHARMM-GUI functionality, allowing the research community to carry out innovative and novel molecular modeling and simulation research. In this talk, I will present the past, present, and future of the CHARMM-GUI development project, and some applications for specific modules will be also discussed.