Removing glutamate from the synaptic cleft is vital for proper function of brain. Excitatory amino acid transporters mediate this process by uptaking neurotransmitter back to cell after its release. The archaeal homolog, GltPh, an aspartate transporter Pyrococcus horikoshii, presents best structurally characterized model family transporters. In order transport, GltPh undergoes elevator-like conformational changes between inward-facing (IF) and outward-facing (OF) states. Here, we...

Significance Membrane transporters rely on large-scale conformational changes for their function. Despite considerable effort, however, details of such structural transitions are largely unknown, leaving many fundamental questions regarding the transport mechanism in this important family membrane proteins unanswered. Here, we present a nonequilibrium approach to characterize transition MsbA, member ATP-binding cassette exporter family, which is involved diverse substrates across membrane....

Abstract Membrane transporters actively translocate their substrate by undergoing large-scale structural transitions between inward- (IF) and outward-facing (OF) states (‘alternating-access’ mechanism). Despite extensive studies, atomic-level mechanistic details of such transitions, as importantly, coupling to chemical events supplying the energy, remain amongst most elusive aspects function these proteins. Here we present a quantitative, description functional thermodynamic cycle for...

The structure of the proline amino acid allows folded polyproline peptides to exist as both left- (PPII) and right-handed (PPI) helices. We have characterized free energy landscapes hexamer, nanomer, tridecamer in gas phase implicit water well explicit hexane 1-propanol for nanomer. To enhance sampling provided by regular molecular dynamics, we used recently developed adaptively biased dynamics method, which describes Landau maps terms relevant collective variables. These maps, a function...

Characterizing large-scale structural transitions in biomolecular systems poses major technical challenges to both experimental and computational approaches. On the side, efficient sampling of configuration space along transition pathway remains most daunting challenge. Recognizing this issue, we introduce a knowledge-based approach toward describing conformational using (i) nonequilibrium, driven simulations combined with work measurements (ii) free energy calculations empirically optimized...

The protein-ligand binding affinity quantifies the strength between a protein and its ligand. Computer modeling simulations can be used to estimate or free energy using data- physics-driven methods combination thereof. Here we discuss purely physics-based sampling approach based on biased molecular dynamics simulations. Our proposed method generalizes simplifies previously suggested stratification strategies that use umbrella other enhanced with additional collective-variable-based...

G-protein coupled receptors (GPCRs), one of the largest superfamilies cell-surface receptors, are heptahelical integral membrane proteins that play critical roles in virtually every organ system. G-protein-coupled operate membranes rich cholesterol, with an imbalance cholesterol level within vicinity GPCR transmembrane domains affecting structure and/or function many GPCRs, a phenomenon has been linked to several diseases. These effects could result indirect changes by altering mechanical...

ATP synthase is the most prominent bioenergetic macromolecular motor in all life forms, utilizing proton gradient across cell membrane to fuel synthesis of ATP. Notwithstanding wealth available biochemical and structural information inferred from years experiments, precise molecular mechanism whereby vacuolar (V-type) fulfills its biological function remains largely fragmentary. Recently, crystallographers provided first high-resolution view activity Enterococcus hirae V

The string method with swarms of trajectories (SMwST) is an algorithm that identifies a physically meaningful transition pathway─a one-dimensional curve, embedded within high-dimensional space selected collective variables. SMwST leans on series short, unbiased molecular dynamics simulations spawned at different locations the discretized path, from whence average dynamic drift determined to evolve toward optimal pathway. However conceptually simple in both its theoretical formulation and...

Within the last 2 decades, severe acute respiratory syndrome coronaviruses 1 and (SARS-CoV-1 SARS-CoV-2) have caused two major outbreaks; yet, for reasons not fully understood, coronavirus disease 2019 pandemic by SARS-CoV-2 has been significantly more widespread than 2003 SARS epidemic SARS-CoV-1, despite striking similarities between these viruses. The SARS-CoV-1 spike proteins, both of which bind to host cell angiotensin-converting enzyme 2, implied be a potential source their...

Since its discovery in 1979, left-handed Z-DNA has evolved from an vitro curiosity to a challenging DNA structure with crucial roles gene expression, regulation and recombination. A fundamental question that puzzled researchers for decades is how the transition B-DNA, prevalent right-handed form of DNA, accomplished. Due complexity B–Z-DNA transition, experimental computational studies have resulted several different, apparently contradictory models. Here, we use molecular dynamics...

By undergoing conformational changes, active membrane transporters alternate between an inward-facing (IF) and outward-facing (OF) state to transport their substrates across cellular membrane. The landscape of transporters, however, could be influenced by environment, the dependence alternating access mechanism on lipid composition has not been understood at molecular level. We have performed extensive set microsecond-level all-atom dynamics (MD) simulations bacterial ATP binding cassette...

Multidrug resistance (MDR) proteins belonging to the ATP-Binding Cassette (ABC) transporter group play a crucial role in export of cytotoxic drugs across cell membranes. These are particularly fascinating due their ability confer drug resistance, which subsequently leads failure therapeutic interventions and hinders successful treatments. One key mechanism by multidrug carry out transport function is through alternating access. This involves intricate conformational changes that enable...