Abstract Motivation: Molecular simulation has historically been a low-throughput technique, but faster computers and increasing amounts of genomic structural data are changing this by enabling large-scale automated of, for instance, many conformers or mutants biomolecules with without range ligands. At the same time, advances in performance scaling now make it possible to model complex biomolecular interaction function manner directly testable experiment. These applications share need fast...

CHARMM27 is a widespread and popular force field for biomolecular simulation, several recent algorithms such as implicit solvent models have been developed specifically it. We here implemented the CHARMM all necessary extended functional forms in GROMACS molecular simulation package, to make CHARMM-specific features available test them combination with techniques time steps, major fields comparison studies GROMACS, various model optimizations, particular effect of Lennard-Jones interactions...

The thermodynamics of hydrogen bond breaking and formation was studied in solutions alcohol (methanol, ethanol, 1-propanol) molecules. An extensive series over 400 molecular dynamics simulations with an aggregate length 900 ns analyzed using analysis technique which (HB) is interpreted as Eyring process, for the Gibbs energy activation ΔG⧧ can be determined from HB lifetime. By performing at different temperatures, we were able to determine enthalpy ΔH⧧ entropy TΔS⧧ this process Van't Hoff...

Abstract When researchers build high‐quality models of protein structure from sequence homology, it is today common to use several alternative target‐template alignments. Several methods can, at least in theory, utilize information multiple templates, and many examples improved model quality have been reported. However, our knowledge, thus far no study has shown that automatic inclusion alignments guaranteed improve without artifacts. Here, we carried out a systematic investigation the...

Fusion peptides from influenza hemagglutinin act on membranes to promote membrane fusion, but the mechanism by which they do so remains unknown. Recent theoretical work has suggested that contact of protruding lipid tails may be an important feature transition state for fusion. If this is so, then fusion would expected tail protrusion in proportion ability corresponding full-length drive mixing assays. We have performed molecular dynamics simulations bilayers, comparing X-31 strain against a...

We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and small-scale dissolution apparatus (μDISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This then guided how stabilize formulation. Indapamide, metolazone, glibenclamide glipizide were selected as model HPMC (Pharmacoat 606) PVP...

Abstract High‐performance implementations of molecular dynamics (MD) simulations play an important role in the study macromolecules. Recent advances both hardware and simulation software have extended accessible time scales significantly, but more complex algorithms used many codes today occasionally make it difficult to understand program flow data structures without at least some knowledge about underlying ideas improve performance. In this review, we discuss currently most areas algorithm...

The absorption of hydrophobic drugs and nutrients from the intestine is principally determined by amount that can be dissolved endogenous fluids present in gut. Human intestinal (HIFs) comprise a complex mixture bile salts, phospholipids, steroids glycerides vary composition fed fasted state between subjects. A number simulated fluid (SIF) compositions have been developed to mimic conditions allow vitro determination drug solubility as proxy for maximum concentration it possible reach. In...

The structure and dynamics of Opa proteins, which we report herein, are responsible for the receptor-mediated engulfment Neisseria gonorrheae or meningitidis by human cells can offer deep understanding into molecular recognition pathogen–host receptor interactions. Such interactions vital to bacterial pathogenesis as well mechanism foreign body entry a cell, may provide insights development targeted pharmaceutical delivery systems. size extracellular loops Opa60 required hybrid refinement...

ABSTRACT Ebolavirus is an enveloped virus causing severe hemorrhagic fever. Its surface glycoproteins undergo proteolytic cleavage and rearrangements to permit membrane fusion cell entry. Here we focus on the glycoprotein's internal loop (FL), critical for low-pH-triggered in endosome. Alanine mutations at L529 I544 particularly double mutation compromised viral entry fusion. The nuclear magnetic resonance (NMR) structures of I544A L529A mutants lipid environments showed significant...

Understanding of peptide aggregation propensity is an important aspect in pharmaceutical development drugs. In this work, methodologies based on all-atom molecular dynamics (AA-MD) simulations and

Abstract Model Quality Assessment Programs (MQAPs) are programs developed to rank protein models. These methods can be trained predict the overall global quality of a model or what local regions in that likely incorrect. In CASP8, we participated with two predictors both and using either consensus information, Pcons, purely structural ProQ. Consistently results previous CASPs, best performance CASP8 was obtained Pcons method. Furthermore, show modification introduced into for improved...

Medium chain fatty acids (MCFA) are digestion products of lipid-rich food and lipid-based formulations, they used as transient permeability enhancers in formulation poorly permeable compounds. These molecules may promote drug absorption by several different processes, including solubilization, increased membrane fluidity, paracellular transport through opening the tight junctions. Therefore, understanding aggregation behavior MCFAs is important. A number studies have measured critical...

Due to the expanding and ageing world population, importance use of medicines is expected increase. However, this will lead a greater impact on ecosystem our health in long term. The concept sustainability rather slowly gaining traction currently still fragmented pharmaceutical field. A consortium researchers from five European universities therefore advocates global, systematic approach places emphasis already early stages drug development, i.e. discovery. According researchers, competent...

The Pcons.net Meta Server (http://pcons.net) provides improved automated tools for protein structure prediction and analysis using consensus. It essentially implements all the steps necessary to produce a high quality model of protein. whole process is fully potential user only submits sequence. For PSI-BLAST detectable targets, an accurate generated within minutes submission. more difficult targets sequence automatically submitted publicly available fold-recognition servers that use...

Biomolecular simulation is a core application on supercomputers, but it exceptionally difficult to achieve the strong scaling necessary reach biologically relevant timescales. Here, we present new paradigm for parallel adaptive molecular dynamics and publicly available implementation: Copernicus. This framework combines performance-leading parallelized three levels (SIMD, threads, message-passing) with kinetic clustering, statistical model building real-time result monitoring. Copernicus...

Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, effects are variable across individuals classes drugs biologics. Here, we examined influence bile compositions on ability membrane incorporation three transient PEs—caprylate, SNAC—using coarse-grained molecular dynamics (CG-MD). The availability free PE monomers, which important near absorption site, to become...

Molecular transport mechanisms of poorly soluble hydrophobic drug compounds to lipid membranes were investigated using molecular dynamics (MD) simulations. The model compound danazol was used investigate the mechanism(s) by which bile micelles delivered it membrane. interactions between membrane and pure aggregates—in form amorphous aggregates nanocrystals—were also studied. Our simulations indicate that formed in intestinal fluid may facilitate incorporation into cellular through two...

Proteins, and in particular whey proteins, have recently been introduced as a promising excipient class for stabilizing amorphous solid dispersions. However, despite the efficacy of approach, molecular mechanisms behind stabilization drug form are not yet understood. To investigate these, we used experimental computational techniques to study impact loading on stability protein-stabilized formulations. β-Lactoglobulin, major component whey, was chosen model protein indomethacin drug....

Efficient delivery of oral drugs is dependent on their solubility in human intestinal fluid, a complex and dynamic fluid that contains colloidal structures composed small molecules. These solubilize poorly water-soluble compounds, increasing apparent solubility, possibly bioavailability. In this study, we conducted coarse-grained molecular dynamics simulations with data from duodenal samples previously acquired five healthy volunteers. these simulations, observed the self-assembly mixed...

The absolute performance of any all-atom molecular dynamics simulation is typically limited by the length individual timesteps taken when integrating equations motion. In GROMACS software, it has for a long time been possible to use so-called virtual sites increase timestep, resulting in large gain efficiency. Up until now, support this approach practice standard 20 amino acids however, shrinking applicability domain sites. MkVsites set python tools which provides convenient way obtain all...

We performed molecular dynamics (MD) simulations to obtain insights into the structure and interactions of colloidal structures present in fasted state intestinal fluid. Drug partitioning interaction were studied with a mixed system bile salt taurocholate (TCH) 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLiPC). Spontaneous aggregation TCH DLiPC from unconstrained MD at united-atom level using Berger/Gromos54A7 force fields demonstrated that intermolecular hydrogen bonding between molecules...