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...

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 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...

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...

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...

Lasso peptides are a unique class of natural products with distinctively threaded structures, conferring exceptional stability against thermal and proteolytic degradation. Despite their promising biotechnological pharmaceutical applications, reported attempts to prepare them by chemical synthesis result in forming the nonthreaded branched-cyclic isomer, rather than desired lassoed structure. This is likely due entropic challenge folding short, motif prior chemically mediated cyclization....

The transport of ions through channels involves multiple rare-event transitions a web interconnected intermediates. Extracting open channel mechanisms generally requires quantifying the relative flux these intermediates in response to range electrochemical gradients. Although this is ideally suited network-based representations, like Markov state models (MSMs), contributions from different pathways and importance network resolution remain areas research. Herein, we use complementary approach...

The transport of ions through channels involves multiple rare-event transitions a web interconnected intermediates. Extracting open channel mechanisms generally requires quantifying the relative flux these intermediates in response to range electrochemical gradients. Although this is ideally suited network-based representations like Markov state models (MSMs), contributions from different pathways and importance network resolution remain areas research. Herein, we use complementary approach...