Abstract Recent studies found that membrane-bound K-Ras dimers are important for biological function. However, the structure and thermodynamic stability of these complexes remained unknown because they hard to probe by conventional approaches. Combining data from a wide range computational experimental approaches, here we describe structure, dynamics, energetics mechanism assembly multiple dimers. Utilizing techniques detection reactive surfaces, protein-protein docking molecular...

Significance The aggregation of the amyloid- <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"><mml:mi>β</mml:mi></mml:math> peptide (A ) into neurotoxic oligomers is central to development Alzheimer’s disease. One possible source their toxicity results from interactions A with neuronal membrane, damaging membrane integrity and thus neurons. However, molecular details these are unclear. Here, we contrast dimerization in solution at membrane. Our clearly indicate that...

Self-assembly of plasma membrane-associated Ras GTPases has major implications to the regulation cell signaling. However, structural basis homo-oligomerization and fractional distribution oligomeric states remained undetermined. We have addressed these issues by deciphering dimers higher-order oligomers K-Ras4B, most frequently mutated isoform in human cancers. focused on constitutively active G12V K-Ras two its variants, K101E K101C/E107C, which respectively destabilize stabilize oligomers....

Despite years of study, the structural or dynamical basis for differential reactivity and oncogenicity Ras isoforms mutants remains unclear. In this we investigated effects amino acid variations on structure dynamics wild type oncogenic G12D, G12V, G13D H- K-Ras proteins. Based data from µs-scale molecular simulations, show that overall proteins similar but there are important differences in interaction networks. We identified residue patterns around canonical switch distal loop regions,...

We conducted over 150 ns of simulation a protegrin-1 octamer pore in lipid bilayer composed palmitoyloleoyl-phosphatidylethanolamine (POPE) and palmitoyloleoyl-phosphatidylglycerol (POPG) lipids mimicking the inner membrane bacterial cell. The simulations improve on model proposed from recent NMR experiments provide coherent understanding molecular mechanism antimicrobial activity. Although tilt somewhat toward peptides, simulated more closely follows barrel-stave than toroidal-pore model....

To investigate the stability and functional role of long-residence water molecules in Q61H variant signaling protein K-ras, we analyzed all available Ras crystal structures conformers derived from a series independent explicit solvent molecular dynamics (MD) simulations totaling 1.76 µs. We show that samples different region phase space presence absence several crystallographically conserved buried molecules. The these waters is coupled with local as well global motions protein, contrast to...

Dimer formation is believed to have a substantial impact on regulating K-Ras function. However, the evidence for dimerization and molecular details of process are scant. In this study, we characterize pseudo-C2-symmetric interface involving effector interacting β2-strand. We used structure matching all-atom dynamics (MD) simulations predict, refine, investigate stability interface. Our MD simulation suggested that β2-dimer potentially stable remains relatively close its initial conformation...

Phosphorylation of tyrosine 32 in K-Ras has been shown to influence function by disrupting the GTPase cycle. To shed light on underlying mechanism and atomic basis this process, we carried out a comparative investigation oncogenic G12D mutant its phosphorylated variant (pTyr32) using all-atom molecular dynamics simulations Markov state models. We show that, despite sharing number common features, pTyr32-G12D exhibit some distinct conformational states fluctuations. In addition notable...

Protegrin peptides are potent antimicrobial agents believed to act against a variety of pathogens by forming nonselective transmembrane pores in the bacterial cell membrane. We have employed 3D Poisson-Nernst-Planck (PNP) calculations determine steady-state ion conduction characteristics such at applied voltages range -100 +100 mV 0.1 M KCl bath solutions. tested pore structures extracted from molecular dynamics (MD) simulations based on an experimentally proposed octomeric structure. The...

Probe-based or mixed solvent molecular dynamics simulation is a useful approach for the identification and characterization of druggable sites in drug targets. However, thus far method has been applied only to soluble proteins. A major reason this potential effect probe molecules on membrane structure. We have developed technique overcome limitation that entails modification force field parameters reduce few pairwise non-bonded interactions between selected atoms bilayer lipids. used...

Polyglutamine expansion at the N-terminus of huntingtin protein exon 1 (Htt-ex1) is closely associated with a number neurodegenerative diseases, which result from aggregation increased polyQ repeat. However, underlying structures and mechanism are still poorly understood. We performed microsecond-long all-atom molecular dynamics simulations to study folding dimerization Htt-ex1 (about 100 residues) non-pathogenic pathogenic lengths, uncovered substantial differences. The monomer adopts long...

Membrane proteins represent a considerable fraction of pharmaceutical drug targets. A computational technique to identify ligand binding pockets in these is therefore great importance. We recently reported such called pMD-membrane that utilizes small molecule probes detect sites and surface hotspots on membrane based probe-based molecular dynamics simulation. The current work extends diverse set organic species can be used as cosolvents during simulation proteins. also describe projection...

Bile acids are powerful detergents that emulsify and solubilize lipids, vitamins, cholesterol other molecules in the biliary tract intestines. It has long been known bile form soluble mixed micelles with lipids. However, detailed thermodynamic structural properties of these not fully understood. This study sheds light on this issue based results from multiple molecular dynamics simulations cholic acid (CA) dodecylphosphocholine (DPC) micelles. We found CA aggregates up to 12 monomers a mean...

Abstract Background Gene expression microarray and other multiplex data hold promise for addressing the challenges of cellular complexity, refined diagnoses discovery well-targeted treatments. A new approach to construction quantification transcriptional regulatory networks (TRNs) is presented that integrates gene cell modeling through information theory. Given a partial TRN time series data, probability density constructed functional course transcription factor (TF) thermodynamic activities...

The Poisson-Boltzmann (PB) equation has been extensively used to analyze the energetics and structure of proteins other significant biomolecules immersed in electrolyte media. A new highly efficient approach for solving PB-type equations that allows modeling many-atoms structures such as encountered cell biology, virology, nanotechnology is presented. We accomplish these efficiencies by reformulating elliptic PB long-time solution an advection-diffusion equation. An modified, memory...

The tetracycline operon is an important gene network component, commonly used in synthetic biology applications because of its switch-like character. At the heart this system highly specific interaction tet repressor protein (TetR) with cognate DNA sequence (tetO). TetR binding on tetO practically stops expression genes downstream by excluding RNA polymerase from promoter and initiating transcription. Mutating alters strength TetR-tetO thus provides a tool to biologists manipulate levels. We...

Continuum models that describe the effects of solvent and biological membrane molecules on structure behavior antimicrobial peptides, holds a promise to improve our understanding mechanisms action these peptides. In such methods, lipid bilayer model is implicitly represented by multiple layers relatively low dielectric constant embedded in high aqueous solvent, while an peptide accounted for cavity with fixed partial charge at center each one its atoms. present work, we investigate ability...

We present relative binding free energy calculations for six antimicrobial peptide-micelle systems, three peptides interacting with two types of micelles. The are the scorpion derived peptide (AMP), IsCT and its analogues. micelles dodecylphosphatidylcholine (DPC) sodium dodecylsulphate (SDS) interfacial electrostatic properties DPC SDS assumed to be similar those zwitterionic mammalian anionic bacterial membrane interfaces, respectively. test hypothesis that strength between micelle can...

The optical characteristics of a simple, planar, single layer, dielectric Mg-based guided mode resonance filter (GMRF) were investigated by means rigorous-coupled wave analysis (RCWA). This has great potential for real-life applications, especially as bio- and environmental sensors. structure the proposed sensor is compact, all its layers can be grown in process. In this paper, we present results on design water pollution violet region visible spectrum. spectral angular sensitivities both...

Oxidative stress is known to play an important role in the pathogenesis of Alzheimer's disease. Moreover, it becoming increasingly evident that plasma membrane neurons plays a modulating aggregation and toxicity amyloid-β peptide (Aβ). In this study, combined interdependent effects oxidation interactions on 42 residues long Aβ isoform are investigated using molecular simulations. Hamiltonian replica exchange dynamics simulations utilized elucidate impact selected oxidized glycine Aβ42 with...

Modeling approaches to the dynamics of a living cell are presented that strongly based on its underlying physical and chemical processes hierarchical spatio-temporal organization. Through inclusion broad spectrum rigorous analysis multiple scale nature cellular dynamics, we attempting advance modeling applications. The presentation focuses our system, which integrates data archiving quantitative physico-chemical information theory provide seamless approach modeling/data endeavor. Thereby...