Gregory A. Voth

Phosphate, an essential metabolite involved in numerous cellular functions, is taken up by proton-coupled phosphate transporters of plants and fungi within the major facilitator family. Similar phosphate transporters have been identified across a diverse range of biological entities, including various protozoan parasites linked to human diseases, breast cancer cells with increased phosphate requirements, and osteoclast-like cells engaged in bone resorption. Prior studies have proposed an overview of the functional cycle of a proton-driven phosphate transporter (PiPT), yet a comprehensive understanding of the proposed reaction pathways necessitates a closer examination of each elementary reaction step within an overall kinetic framework. In this work, we leverage kinetic network modeling in conjunction with a "bottom-up" molecular dynamics approach to show how such an approach can characterize the proton …

Amino acid ionic liquids (AAILs) are promising green materials for CO2 capture and conversion due to their large chemical structural tunability. However, the structural understanding of the AAILs underlying the CO2 reaction dynamics remains uncertain. Herein, we examine the steric effects of AAIL anions with various chemical structures on CO2 capture behavior. Based on ab initio free-energy sampling, we assess reaction mechanisms for carbamate formation via a two-step reaction pathway with a zwitterion intermediate undergoing dynamic proton transfer. Our results show that free-energy barriers for carbamate formation can be significantly reduced as the degree of steric hindrance of the anions decreases. Further analyses reveal that reduced steric hindrance of anions causes markedly stronger intermolecular interactions between zwitterion and anions, leading to an increased kinetically favorable …

The enormous impact on public health and the economy of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection encourages unprecedented research worldwide to eradicate the virus. The SARS-CoV-2 virion is composed of four major structural proteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N). The M protein is the most abundant structural protein in the virion surface. It plays a central role in assembly and budding processes, whereas the N protein packages the viral genomic RNA into a ribonucleoprotein complex and interacts with M at the assembly sites. Our study investigates the protein-protein and protein-lipid interactions of M and N proteins in biologically relevant complex membrane models. We performed atomistic molecular dynamics simulations using recent experimental structures of M and N proteins. We identified important …

The HIV-1 assembly process begins with a newly synthesized Gag polyprotein being targeted to the inner leaflet of the plasma membrane of the infected cells to form immature viral particles. Gag–membrane interactions are mediated through the myristoylated (Myr) N-terminal matrix (MA) domain of Gag, which eventually multimerize on the membrane to form trimers and higher order oligomers. The study of the structure and dynamics of peripheral membrane proteins like MA has been challenging for both experimental and computational studies due to the complex transient dynamics of protein–membrane interactions. Although the roles of anionic phospholipids (PIP2, PS) and the Myr group in the membrane targeting and stable membrane binding of MA are now well-established, the cooperative interactions between the MA monomers and MA-membrane remain elusive in the context of viral assembly and release …

Vasodilator‐stimulated phosphoprotein (VASP) family proteins play a crucial role in mediating the actin network architecture in the cytoskeleton. The Ena/VASP homology 2 (EVH2) domain in each of the four identical arms of the tetrameric VASP consists of a loading poly‐Pro region, a G‐actin‐binding domain (GAB), and an F‐actin‐binding domain (FAB). Together, the poly‐Pro, GAB, and FAB domains allow VASP to bind to sides of actin filaments in a bundle, and recruit profilin–G‐actin to processively elongate the filaments. The atomic resolution structure of the ternary complex, consisting of the loading poly‐Pro region and GAB domain of VASP with profilin–actin, has been solved over a decade ago; however, a detailed structure of the FAB‐F‐actin complex has not been resolved to date. Experimental insights, based on homology of the FAB domain with the C region of WASP, have been used to hypothesize that …

During the HIV-1 assembly process, the Gag polyprotein multimerizes at the producer cell plasma membrane, resulting in the formation of spherical immature virus particles. Gag-genomic RNA (gRNA) interactions play a crucial role in the multimerization process, which is yet to be fully understood. We performed large-scale all-atom molecular dynamics simulations of membrane-bound full-length Gag dimer, hexamer, and 18-mer. The inter-domain dynamic correlation of Gag, quantified by the heterogeneous elastic network model applied to the simulated trajectories, is observed to be altered by implicit gRNA binding, as well as the multimerization state of the Gag. The lateral dynamics of our simulated membrane-bound Gag proteins, with and without gRNA binding, agree with prior experimental data and help to validate our simulation models and methods. The gRNA binding is observed to affect mainly the SP1 …

Endocytosis provides extensive insights into the processes by which cells remodel their membranes in response to their surroundings. While studies of endocytosis primarily focus on clathrin-mediated endocytosis (CME), several clathrin-independent pathways occur under distinct timescales and conditions, indicating fundamentally different physics at play. Two such pathways, fast endophilin-mediated endocytosis (FEME) and ultra-fast endocytosis (UFE), occur up to three orders of magnitudes faster than observed for CME and have been implicated in neurodegenerative diseases and cancers. These pathways are primarily mediated by the BAR domain protein endophilin, an important membrane-remodeling protein. The different domains of endophilin both promote and suppress scission and vesiculation, as well as induce varied membrane morphologies. In addition, endophilin recruits downstream partners like …

Caveolin is a monotopic membrane protein, widely expressed in metazoa and responsible for enigmatic curved membrane structures known as caveolae. This functionality and capacity for membrane deformation are mediated by the assembly of caveolins into oligomeric structures. Recently, the first high-resolution structure of purified human caveolin assemblies, CAV8S, revealed a unique organization of 11 caveolin protomers arranged in a tightly packed, radially symmetric spiral disc of∼ 15 nm diameter and 3 nm thickness. Among several unusual features, one face and all sides of this disc are almost exclusively hydrophobic, suggesting that it inserts deeply into lipid bilayers, displacing∼ 250 phospholipids from the cytosolic leaflet. Here, using a combination of coarse-grained and atomistic simulations, we evaluate the biophysical characteristics and stability of this arrangement. Our observations strongly …