An implicit solvent model is presented that couples hydrophobic, dispersion, and electrostatic solvation energies by minimizing the system Gibbs free energy with respect to volume exclusion function. The accessible surface output of theory. method illustrated simple solutes on different length scales captures sensitivity hydration particular form solute-solvent interactions in agreement recent computer simulations.

Significance The influenza A M2 channel (AM2) transports protons into the virus upon acid activation. It is an important pharmacological target as well a prototypical case to study proton conduction through biological channels. current work provides most complete computational characterization date of physical basis for activation mechanism AM2 channel. Our results show that lowering pH value gradually opens Trp41 gate and decreases deprotonation barrier His37 tetrad, leading result also...

Significance The uptake of nutrients from the environment is an essential process that achieved in most cells through use secondary active transporters. POT family proton-coupled peptide transporters are one diverse nutrient systems, recognizing amino acids, peptides, nitrate, and seed-defense compounds. A long-standing question how this achieves such ligand diversity. high-resolution crystal structure combined with multiscale molecular dynamics simulations demonstrate water molecules able...

Lasso peptides make up a class of natural products characterized by threaded structure. Given their small size and stability, chemical synthesis would offer tremendous potential for the development novel therapeutics. However, accessibility pre-folded lasso architecture has limited this advance. To better understand folding process

Recent studies on the solvation of atomistic and nanoscale solutes indicate that a strong coupling exists between hydrophobic, dispersion, electrostatic contributions to free energy, facet not considered in current implicit solvent models. We suggest theoretical formalism which accounts for by minimizing Gibbs energy with respect volume exclusion function. The resulting differential equation is similar Laplace-Young geometrical description capillary interfaces, but extended microscopic...

A short-range effective potential for long-range electrostatic interactions in homogeneously disordered condensed phase systems has been determined with a novel approach to coarse-graining interaction space. As opposed the system resolution, this "coarsens" system's by mapping multiple configurations of an accurate atomistic onto more efficient, force-matching (FM) method. Developing empirical manner is fundamentally different from existing strategies because it utilizes condensed-phase (as...

Grotthuss shuttling of an excess proton charge defect through hydrogen bonded water networks has long been the focus theoretical and experimental studies. In this work we show that there is a related process in which molecules move ("shuttle") hydrated order to wet path ahead for subsequent migration. This illustrated reactive molecular dynamics simulations transport hydrophobic nanotube, penetrates region. Surprisingly, before enters it starts "shooting" into otherwise dry space via...

Significance The M2 channel in the influenza A virus is one of three commonly targeted proteins viral membrane. Proton permeation across acidifies virion, releasing RNA and core proteins. This work constitutes, to our knowledge, first complete characterization this process by multiscale computer simulation, results are quantitative agreement with prior experimental measurements. simulations confirm that mechanism involves a “shuttling” protons through His37 tetrad rate-limiting step...

Permeability (Pm) across biological membranes is of fundamental importance and a key factor in drug absorption, distribution, development. Although the majority drugs will be charged at some point during oral delivery, our understanding membrane permeation by species limited. The canonical model assumes that only neutral molecules partition into passively permeate membranes, but there mounting evidence these processes are also facile for certain species. However, it unknown whether such...

Cytochrome c oxidase (CcO) reduces oxygen to water and uses the released free energy pump protons across membrane. We have used multiscale reactive molecular dynamics simulations explicitly characterize (with free-energy profiles calculated rates) internal proton transport events that enable pumping during first steps of oxidation fully reduced enzyme. Our results show from amino acid residue E286 both loading site (PLS) binuclear center (BNC) are thermodynamically driven by electron...

Although it has long been recognized that multiple water molecules strongly associate with an extra proton in bulk water, some models and conceptual frameworks continue to utilize the classical hydronium ion (H3O+) as a fundamental building block. In this work, nature of aqueous systems is examined using ab initio energy decomposition analysis (EDA) evaluates both magnitude energetic stabilization due charge transfer among H3O+ surrounding molecules. The EDA performed on structures extracted...

An important challenge in the simulation of biomolecular systems is a quantitative description protonation and deprotonation process amino acid residues. Despite seeming simplicity adding or removing positively charged hydrogen nucleus, simulating actual protonation/deprotonation inherently difficult. It requires both explicit treatment excess proton, including its charge defect delocalization Grotthuss shuttling through inhomogeneous moieties (water residues), extensive sampling coupled...

Despite several years of research, the ion exchange mechanisms in chloride/proton antiporters and many other coupled transporters are not yet understood at molecular level. Here, we present a novel approach to kinetic modeling apply it ClC-ec1. Our multiscale model is developed by (1) calculating state-to-state rate coefficients with reactive polarizable dynamics simulations, (2) optimizing these rates global network, (3) predicting new electrophysiological results. The shows that robust...

Estimating the permeability coefficient of small molecules through lipid bilayer membranes plays an important role in development effective drug candidates. In silico simulations can produce acceptable relative coefficients for a series molecules; however, absolute from are usually off by orders magnitude. addition to differences between bilayers used vitro and silico, poor convergence permeation free energy profiles over-simplified diffusion models have contributed these discrepancies. this...

Implicit solvent models are a standard tool for assessing the electrostatics of biomolecular systems. The accuracy quantitative predictions, such as pKa values, transfer free energies, binding and solvation forces, is strongly dependent on one's choice continuum parameters: solute charges, dielectric coefficient, radii, which define boundary. To ensure accuracy, these parameters can be benchmarked against explicit simulations. Here we present two sets optimized radii to either abrupt or...

Significance Understanding the molecular mechanism that enables high proton-pumping efficiency of cytochrome c oxidase (C O) is not only fundamentally important but also potentially useful in providing design principles for bio-inspired materials. To this end, much effort has been devoted to D-channel mutants C O impair proton pumping. In study, we have used multiscale reactive dynamics simulations explicitly characterize free-energy profiles transport (PT) through several mutants. Our...

The ClC family of transmembrane proteins functions throughout nature to control the transport Cl- ions across biological membranes. ClC-ec1 from Escherichia coli is an antiporter, coupling and H+ in opposite directions driven by concentration gradients ions. Despite keen interest this protein, molecular mechanism Cl-/H+ has not been fully elucidated. Here, we have used multiscale simulation help identify essential coupling. We find that highest barrier for proton (PT) intra- extracellular...