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Vanegas, Juan M.

Publications and source records attributed to Vanegas, Juan M..

8 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Metadynamics simulations reveal mechanisms of Na + and Ca 2+ transport in two open states of the channelrhodopsin chimera, C1C2

Cation conducting channelrhodopsins (ChRs) are a popular tool used in optogenetics to control the activity of excitable cells and tissues using light. ChRs with altered ion selectivity are in high demand for use in different cell types and for other specialized applications. However, a detailed mechanism of ion permeation in ChRs is not fully resolved. Here, we use complementary experimental and computational methods to uncover the mechanisms of cation transport and valence selectivity through the channelrhodopsin chimera, C1C2, in the high- and low-conducting open states. Electrophysiology measurements identified a single-residue substitution within the central gate, N297D, that increased Ca 2+ permeability vs. Na + by nearly two-fold at peak current, but less so at stationary current. We then developed molecular models of dimeric wild-type C1C2 and N297D mutant channels in both open states and calculated the PMF profiles for Na + and Ca 2+ permeation through each protein using well-tempered/multiple-walker metadynamics. Results of these studies agree well with experimental measurements and demonstrate that the pore entrance on the extracellular side differs from original predictions and is actually located in a gap between helices I and II. Cation transport occurs via a relay mechanism where cations are passed between flexible carboxylate sidechains lining the full length of the pore by sidechain swinging, like a monkey swinging on vines. In the mutant channel, residue D297 enhances Ca 2+ permeability by mediating the handoff between the central and cytosolic binding sites via direct coordination and sidechain swinging. We also found that altered cation binding affinities at both the extracellular entrance and central binding sites underly the distinct transport properties of the low-conducting open state. This work significantly advances our understanding of ion selectivity and permeation in cation channelrhodopsins and provides the insights needed for successful development of new ion-selective optogenetic tools.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Nanoconfinement of Carbon Dioxide within Interfacial Aqueous/Ionic Liquid Systems

Nanoporous, gas-selective membranes have shown encouraging results for the removal of CO 2 from flue gas, yet the optimal design for such membranes is often unknown. Therefore, we used molecular dynamics simulations to elucidate the behavior of CO 2 within aqueous and ionic liquid (IL) systems ([EMIM][TFSI] and [OMIM][TFSI]), both confined individually and as an interfacial aqueous/IL system. We found that within aqueous systems the mobility of CO 2 is reduced due to interactions between the CO 2 oxygens and hydroxyl groups on the pore surface. Within the IL systems, we found that confinement has a greater effect on the [EMIM][TFSI] system as opposed to the [OMIM][TFSI] system. Paradoxically, the larger and more asymmetrical [OMIM]+ molecule undergoes less efficient packing, resulting in fewer confinement effects. Finally, free energy surfaces of the nanoconfined aqueous/IL interface demonstrate that CO 2 will transfer spontaneously from the aqueous to the IL phase.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Transport and Energetics of Carbon Dioxide in Ionic Liquids at Aqueous Interfaces

A major hurdle in utilizing carbon dioxide (CO 2 ) lies in separating it from industrial flue gas mixtures and finding suitable storage methods that enable its application in various industries. To address this issue, we utilized a combination of molecular dynamics simulations and experiments to investigate the behavior of CO 2 in common room-temperature ionic liquids (RTIL) when in contact with aqueous interfaces. Here, our investigation of RTILs, [EMIM][TFSI] and [OMIM][TFSI], and their interaction with a pure water layer mimics the environment of a previously developed ultrathin enzymatic liquid membrane for CO 2 separation. We analyzed diffusion constants and viscosity, which reveals that CO 2 molecules exhibit faster mobility within the selected ILs compared to what would be predicted solely based on the viscosity of the liquids using the standard Einstein–Stokes relation. Moreover, we calculated the free energy of translocation for various species across the aqueous–IL interface, including CO 2 and HCO 3 – . Free energy profiles demonstrate that CO 2 exhibits a more favorable partitioning behavior in the RTILs compared to that in pure water, while a significant barrier hinders the movement of HCO 3 – from the aqueous layer. Experimental measurement of the CO 2 transport in the RTILs corroborates the model. These findings strongly suggest that hydrophobic RTILs could serve as a promising option for selectively transporting CO 2 from aqueous media and concentrating it as a preliminary step toward storage.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Energetics of high temperature degradation of fentanyl into primary and secondary products

Fentanyl is a synthetic opioid used for managing chronic pain. Due to its higher potency (50–100×) than morphine, fentanyl is also an abused drug. A sensor that could detect illicit fentanyl by identifying its thermally degraded fragments would be helpful to law enforcement. While experimental studies have probed the thermal degradation of fentanyl, little theoretical work has been done to understand the mechanism. Here, we studied the thermal degradation pathways of fentanyl using extensive ab initio molecular dynamics simulations combined with enhanced sampling via multiple-walker metadynamics. We calculated the free energy profile for each bond suggested earlier as a potential degradation point to map the thermodynamic driving forces. In conclusion, we also estimated the forward attempt rate of each bond degradation reaction to gain information about degradation kinetics.

Poudel, Bharat↗
DOE OSTI2021

Inhibitors for targeting flaviviruses

The present invention relates to methods for identifying candidate therapeutics for a disease caused by a viral envelope protein. In particular, the method can include contacting a test envelope protein with the candidate and determining its activity.

Kent, Michael S.↗
DOE OSTI2020

Hydration Mimicry by Membrane Ion Channels

Ions transiting biomembranes might pass readily from water through ion-specific membrane proteins if these protein channels provide environments similar to the aqueous solution hydration environment. In fact, bulk aqueous solution is an important reference condition for the ion permeation process. Assessment of this hydration mimicry concept depends on understanding the hydration structure and free energies of metal ions in water in order to provide a comparison for the membrane channel environment. To refine these considerations, we review local hydration structures of ions in bulk water and the molecular quasi-chemical theory that provides hydration free energies. In doing so, we note some current views of ion binding to membrane channels and suggest new physical chemical calculations and experiments that might further clarify the hydration mimicry concept.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗