Phase-Dependent Adsorption of Myelin Basic Protein to Phosphatidylcholine Lipid Bilayers.

The dense packing of opposite cytoplasmic surfaces of the lipid-enriched myelin membrane, responsible for the proper saltatory conduction of nerve impulses through axons, is ensured by the adhesive properties of myelin basic protein (MBP). Although preferentially interacting with negatively charged phosphatidylserine (PS) lipids, as an intrinsically disordered protein, it can easily adapt its shape to its immediate environment and thus adsorb to domains made of zwitterionic phosphatidylcholine (PC) lipids. As the molecular-level interaction pattern between MBP and PC lipid membranes suffers from scarce characterization, an experimental and computational study of multilamellar liposomes (MLVs) composed of 1,2-dipalmitoyl--glycero-3-phosphocholine (DPPC) in the presence of bovine MBP is presented here.

Deciphering the origin of the melting profile of unilamellar phosphatidylcholine liposomes by measuring the turbidity of its suspensions.

The elucidation of the thermal properties of phosphatidylcholine liposomes is often based on the analysis of the thermal capacity profiles of multilamellar liposomes (MLV), which may qualitatively disagree with those of unilamellar liposomes (LUV). Experiments and interpretation of LUV liposomes is further complicated by aggregation and lamellarization of lipid bilayers in a short time period, which makes it almost impossible to distinguish the signatures of the two types of bilayers. To characterize independently MLV and LUV of 1,2-dipalmitoyl--glycero-3-phosphocholine (DPPC), the latter were prepared with the addition of small amounts of 1,2-dipalmitoyl--glycero-3-phosphatidylglycerol (DPPG) which, due to the sterical hindrance and negative charge at a given pH value, cause LUV repellence and contribute to their stability.

Perturbation Free-Energy Toolkit: An Automated Alchemical Topology Builder.

Free-energy calculations play an important role in the application of computational chemistry to a range of fields, including protein biochemistry, rational drug design, or materials science. Importantly, the free-energy difference is directly related to experimentally measurable quantities such as partition and adsorption coefficients, water activity, and binding affinities. Among several techniques aimed at predicting free-energy differences, perturbation approaches, involving the alchemical transformation of one molecule into another through intermediate states, stand out as rigorous methods based on statistical mechanics.

Exploring the structure and dynamics of proteins in soil organic matter.

Alongside inorganic materials, water, and air, soil organic matter (SOM) is one of the major components of soil and has tremendous influence on the environment given its vital role in the carbon cycle. Many soil dwelling organisms like plants, fungi and bacteria excrete proteins, whose interaction with SOM is poorly understood on an atomistic level. In this study, molecular dynamics simulations were used to investigate selected proteins in soil models of different complexity from simple co-solvent molecules to Leonardite humic acids (LHA).

Optimization of Alchemical Pathways Using Extended Thermodynamic Integration.

Thermodynamic integration (TI) is a commonly used method to determine free-energy differences. One of its disadvantages is that many intermediate λ-states need to be sampled in order to be able to integrate accurately over ⟨∂/∂λ⟩. Here, we use the recently introduced extended TI to study alternative parameterizations of (λ) and its influence on the smoothness of the ⟨∂/∂λ⟩ curves as well as the efficiency of the simulations.

Vienna soil organic matter modeler 2 (VSOMM2).

Soil Organic Matter (SOM) plays an important role in several biogeochemical processes by directly affecting the microbial activity, soil aggregation, plant growth and carbon storage. Despite of its importance, our understanding of its composition and structure is still incomplete. Several experiments using elemental analysis, nuclear magnetic resonance (NMR) and mass spectrometry (MS) shed light on the structure of organic matter.

Molecular modelling of sorption processes of a range of diverse small organic molecules in Leonardite humic acid.

Unlabelled: Soil organic matter (SOM) is abundant in the environment and plays an important role in several biogeochemical processes, including microbial activity, soil aggregation, plant growth and carbon storage. One of its key functions is the retention and release of various chemical compounds, primarily governed by the sorption process, which strongly affects the environmental fate of nutrients and pollutants. Sorption largely depends on the composition of SOM, as well as its structure, dynamics and the thermodynamic conditions.

Toward Automated Free Energy Calculation with Accelerated Enveloping Distribution Sampling (A-EDS).

Free-energy perturbation (FEP) methods are commonly used in drug design to calculate relative binding free energies of different ligands to a common host protein. Alchemical ligand transformations are usually performed in multiple steps which need to be chosen carefully to ensure sufficient phase-space overlap between neighboring states. With one-step or single-step FEP techniques, a single reference state is designed that samples phase-space not only representative of a full transformation but also ideally resembles multiple ligand end states and hence allows for efficient multistate perturbations.

Enhancing the promiscuity of a member of the Caspase protease family by rational design.

The N-terminal cleavage of fusion tags to restore the native N-terminus of recombinant proteins is a challenging task and up to today, protocols need to be optimized for different proteins individually. Within this work, we present a novel protease that was designed in-silico to yield enhanced promiscuity toward different N-terminal amino acids. Two mutations in the active-site amino acids of human Caspase-2 were determined to increase the recognition of branched amino-acids, which show only poor binding capabilities in the unmutated protease.

Correcting electrostatic artifacts due to net-charge changes in the calculation of ligand binding free energies.

Alchemically derived free energies are artifacted when the perturbed moiety has a nonzero net charge. The source of the artifacts lies in the effective treatment of the electrostatic interactions within and between the perturbed atoms and remaining (partial) charges in the simulated system. To treat the electrostatic interactions effectively, lattice-summation (LS) methods or cutoff schemes in combination with a reaction-field contribution are usually employed.

Polarization Effects in Simulations of Kaolinite-Water Interfaces.

Computational models of clay minerals and their interactions with the surrounding medium are highly valuable to study adsorption processes at an atomistic resolution, which may be relevant in different areas such as chromatography, environmental chemistry, and so forth. In this work, we analyzed the effect of the treatment of long-range interactions on the polarization of kaolinite-water interfacial systems in terms of structural, electric and dynamic properties, and hydrogen bonds. When using conventional three-dimensional (3D) Ewald summation, water molecules were more structured on the alumina interface of the kaolinite compared to simulations, in which the periodicity perpendicular to the plane was effectively removed.

The two cathepsin B-like proteases of Arabidopsis thaliana are closely related enzymes with discrete endopeptidase and carboxydipeptidase activities.

The genome of the model plant Arabidopsis thaliana encodes three paralogues of the papain-like cysteine proteinase cathepsin B (AtCathB1, AtCathB2 and AtCathB3), whose individual functions are still largely unknown. Here we show that a mutated splice site causes severe truncations of the AtCathB1 polypeptide, rendering it catalytically incompetent. By contrast, AtCathB2 and AtCathB3 are effective proteases which display comparable hydrolytic properties and share most of their substrate specificities.

Ion-induced modification of the sucrose network and its impact on melting of freeze-dried liposomes. DSC and molecular dynamics study.

Disaccharides play an important role in survival of anhydrobiotic organisms during extreme environmental conditions. A key protection feature is their capability to form the hydrogen bond (HB) network in a similar fashion as the one made by water. Since various ions also affect the HB network in completely hydrated systems, it is of a great interest to understand how they impact preservation when incorporated in a disaccharide network.

Molecular Dynamics Simulations of the Standard Leonardite Humic Acid: Microscopic Analysis of the Structure and Dynamics.

Humic substances (HS) are abundant in the environment and play an important role in a number of biogeochemical processes including microbial activity, soil aggregation, plant growth, the retention and release of nutrients, the environmental fate of pollutants, and carbon storage. They are flexible, relatively small molecules forming supramolecular structures through weak interactions. Despite the great importance of understanding their behavior at the atomic level, computational modeling, a premier high-resolution technique providing great level of detail, has been surprisingly little-employed to study humic substances.

Effect of Oxidative Damage on the Stability and Dimerization of Superoxide Dismutase 1.

During their life cycle, proteins are subject to different modifications involving reactive oxygen species. Such oxidative damage to proteins may lead to the formation of insoluble aggregates and cytotoxicity and is associated with age-related disorders including neurodegenerative diseases, cancer, and diabetes. Superoxide dismutase 1 (SOD1), a key antioxidant enzyme in human cells, is particularly susceptible to such modifications.

Are current atomistic force fields accurate enough to study proteins in crowded environments?

The high concentration of macromolecules in the crowded cellular interior influences different thermodynamic and kinetic properties of proteins, including their structural stabilities, intermolecular binding affinities and enzymatic rates. Moreover, various structural biology methods, such as NMR or different spectroscopies, typically involve samples with relatively high protein concentration. Due to large sampling requirements, however, the accuracy of classical molecular dynamics (MD) simulations in capturing protein behavior at high concentration still remains largely untested.

Trichoplaxin - a new membrane-active antimicrobial peptide from placozoan cDNA.

A method based on the use of signal peptide sequences from antimicrobial peptide (AMP) precursors was used to mine a placozoa expressed sequence tag database and identified a potential antimicrobial peptide from Trichoplax adhaerens. This peptide, with predicted sequence FFGRLKSVWSAVKHGWKAAKSR is the first AMP from a placozoan species, and was named trichoplaxin. It was chemically synthesized and its structural properties, biological activities and membrane selectivity were investigated.

A systematic framework for molecular dynamics simulations of protein post-translational modifications.

By directly affecting structure, dynamics and interaction networks of their targets, post-translational modifications (PTMs) of proteins play a key role in different cellular processes ranging from enzymatic activation to regulation of signal transduction to cell-cycle control. Despite the great importance of understanding how PTMs affect proteins at the atomistic level, a systematic framework for treating post-translationally modified amino acids by molecular dynamics (MD) simulations, a premier high-resolution computational biology tool, has never been developed. Here, we report and validate force field parameters (GROMOS 45a3 and 54a7) required to run and analyze MD simulations of more than 250 different types of enzymatic and non-enzymatic PTMs.

Microscopic analysis of protein oxidative damage: effect of carbonylation on structure, dynamics, and aggregability of villin headpiece.

One of the most important irreversible oxidative modifications of proteins is carbonylation, the process of introducing a carbonyl group in reaction with reactive oxygen species. Notably, carbonylation increases with the age of cells and is associated with the formation of intracellular protein aggregates and the pathogenesis of age-related disorders such as neurodegenerative diseases and cancer. However, it is still largely unclear how carbonylation affects protein structure, dynamics, and aggregability at the atomic level.

Knowledge-based computational methods for identifying or designing novel, non-homologous antimicrobial peptides.

We describe computational approaches for identifying promising lead candidates for the development of peptide antibiotics, in the context of quantitative structure-activity relationships (QSAR) studies for this type of molecule. A first approach deals with predicting the selectivity properties of generated antimicrobial peptide sequences in terms of measured therapeutic indices (TI) for known antimicrobial peptides (AMPs). Based on a training set of anuran AMPs, the concept of sequence moments was used to construct algorithms that could predict TIs for a second test set of natural AMPs and could also predict the effect of point mutations on TI values.