Developing and applying new theoretical and computational methods to study complex condensed phase systems
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Multi-scale Coarse-graining (MS-CG) Force Matching (FM) code is now publicly available for download
ClC-ec1, a Cl- /H+ antiporter, is critical for maintaining ion concentrations and PH gradients in bacteria in acidic environments. In this work, we computationally characterized the rate-limiting step of the overall proton transport process in ClC-ec1 and the essential mechanism of the Cl-/H+ coupling. We found that the highest barrier for PT is located at the deprotonation of E148, and this barrier is significantly reduced by the binding of Cl- in the central site, which displaces E148 and thereby facilitates its deprotonation.
Molecular Modeling and Assignment of IR Spectra of the Hydrated Excess Proton in Isotopically Dilute Water
We developed a mixed quantum-classical model for the vibrational spectroscopy of the excess proton in isotopically dilute water. The model is useful for decomposing IR spectra into contributions from different aqueous proton configurations as validated by our experimental collaborator Andrei Tokmakoff (UChicago). We find that the shift from Eigen to Zundel-like configurations is distinguished by a decrease in the O—H transition frequency.
The influenza A M2 channel (AM2) transports protons into the influenza virus upon acid activation. MS-RMD simulations were performed to characterize the free energy profiles of the proton transport events in the M2 channel. Our results show that decreasing pH causes the Trp41 gate to open, which decreases the deprotonation barrier of the His37 tetrad. This leads to channel activation, which is characterized by increased proton conductance.
Transition-Tempered Metadynamics is a Promising Tool for Studying the Permeation of Drug-like Molecules through Membranes
The recently developed transition-tempered metadynamics (TTMetaD) has been proven to converge asymptotically without sacrificing exploration of the collective variable space in the early stages of simulations. We applied TTMetaD to study the permeation of drug-like molecules through a lipid bilayer to investigate its usefulness in medicinal chemistry. Compared to other enhanced sampling methods, TTMetaD is able to predict the most accurate and reliable estimate of the potential of mean force in the early stages of the simulations. We also show that using multiple randomly initialized replicas allows convergence analysis and provides an efficient means to converge the simulations in shorter wall times and CPU times.
Bin/Amphiphysin/Rvs (BAR) domain proteins control the curvature of lipid membranes in endocytosis, trafficking, cell motility, and the formation of complex subcellular structures. By combining quantitative microscopy with analytical modeling, we demonstrate that a highly curved BAR protein endophilin nucleates its scaffolds at the ends of a membrane tube, unlike the weaker curving protein centaurin, which binds evenly along the tube’s length. Our work implies that local protein–membrane interactions can affect the specific localization of proteins on membrane-remodeling sites.
We used coarse-grained molecular simulations to investigate the way N-BAR proteins interact with one another on the surface of the membrane and generate its curvature. We show a striking assembly of proteins into linear aggregates and meshes that not only helps in understanding how subsequent membrane remodeling may occur, but demonstrates a mechanism for their very rapid recruitment, crucial for e.g. synaptic transmission.
We discuss the relationship between coarse-grained (CG) observables and the corresponding fine-grained (FG) or experimental observables in the framework of systematic bottom-up CG modeling. The importance of this issue is illustrated with a simple polymer system that has implications for the coarse-graining of intramolecular degrees of freedom.
Many crucial biological processes, such as cell division, protein trafficking, and cell signaling, involve large-scale membrane shape and topology changes that are facilitated by complex membrane-protein interactions. In this Review we discuss the recent advances of our group in multiscale computational approaches for studying protein-mediated large-scale membrane remodeling.
We used MS-RMD simulations to characterize the free energy profiles of the proton transport events in the cytochrome c oxidase (CcO) that enable proton pumping and chemical reaction. Our results show that the transfer of both the pumped and chemical protons are thermodynamically driven by electron transfer, and explain how proton back leakage is avoided by kinetic gating.