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1.
Glycobiology ; 30(2): 86-94, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31616921

##### RESUMO

Moraxella catarrhalis (M. catarrhalis) is a pathogenic gram-negative bacterium that causes otitis media and sinusitis in children. Three major serotypes A, B and C are identified to account for approximately 95% of the clinical isolates. Understanding the conformational properties of different serotypes of M. catarrhalis provides insights into antigenic determinants. In this work, all-atom molecular dynamics simulations were conducted for M. catarrhalis lipooligosaccharide (LOS) bilayer systems and oligosaccharides (OS) in water solution to investigate the conformational similarities and differences of three serotypes. For up to 10 neutral monosaccharides in the core part, the conformational ensembles described by the pair-wise root mean square deviation distributions are similar among the three serotypes of either the LOS or OS. At the central ß-($1\to4$)-linkage, anti-$\psi$ conformation in conjunction with the gauche-gauche (g-) conformation of the central trisubstituted glucosyl residue is observed as the dominant conformation to sustain the structural characteristics of M. catarrhalis three types, which is further supported by calculated transglycosidic ${}^3{J}_{C,H}\Big({\psi}_H\Big)$ of serotype A in comparison to experimental data. Interestingly, the conformational variability of three serotypes is more restricted for the OS in water solution than that in the LOS bilayer systems. The LOS-LOS interactions in the bilayer systems are responsible for the increased conformational diversity despite of tight packing. Solvent-accessible surface area analysis suggests that a trisaccharide attached to the ß-($1\to 6$)-linked sugar in all three serotypes of LOS could be the common epitope and have the possibility to interact with antibodies.

2.
J Comput Chem ; 41(5): 415-420, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31329318

##### RESUMO

The double electron-electron resonance (DEER) is a powerful structural biology technique to obtain distance information in the range of 18 to 80 å by measuring the dipolar coupling between two unpaired electron spins. The distance distributions obtained from the experiment provide valuable structural information about the protein in its native environment that can be exploited using restrained ensemble molecular dynamics (reMD) simulations. We present a new tool DEER Facilitator in CHARMM-GUI that consists of two modules Spin-Pair Distributor and reMD Prepper to setup simulations that utilize information from DEER experiments. Spin-Pair Distributor provides a web-based interface to calculate the spin-pair distance distribution of labeled sites in a protein using MD simulations. The calculated distribution can be used to guide the selection of the labeling sites in experiments as well as validate different protein structure models. reMD Prepper facilities the setup of reMD simulations using different types of spin labels in four different environments including vacuum, solution, micelle, and bilayer. The applications of these two modules are demonstrated with several test cases. Spin-Pair Distributor and reMD Prepper are available at http://www.charmm-gui.org/input/deer and http://www.charmm-gui.org/input/deerre. DEER Facilitator is expected to facilitate advanced biomolecular modeling and simulation, thereby leading to an improved understanding of the structure and dynamics of complex biomolecular systems based on experimental DEER data. © 2019 Wiley Periodicals, Inc.

3.
J Phys Chem B ; 123(27): 5700-5708, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31260306

##### RESUMO

Protein-lipopolysaccharide (LPS) interactions play an important role in providing a stable outer membrane to Gram-negative bacteria. However, the LPS molecules are highly viscous, and sampling LPS motions is thus challenging on a microsecond time scale in simulations. To this end, we introduce a new protocol to randomly allow the LPS molecules to self-assemble around the protein and thereby reduce the starting bias in the simulations. Here we present all-atom molecular dynamics simulations of the OmpE36 porin in an outer membrane model which sum up to a simulation time of more than 20 µs and identify the geometrical properties of the first LPS shell and the role of calcium ions in LPS binding to the protein. The simulations reproduce LPS binding to the porin observed in a recently determined crystal structure but not as compact as in the crystal structure. In addition, the influence of the outer membrane environment on the protein dynamics was analyzed. Our findings highlight the role of divalent cations in stabilizing the binding between proteins and LPS molecules in the outer membrane of Gram-negative bacteria.

4.
J Comput Chem ; 40(7): 893-899, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30677169

##### RESUMO

Nanodiscs are discoidal protein-lipid complexes that have wide applications in membrane protein studies. Modeling and simulation of nanodiscs are challenging due to the absence of structures of many membrane scaffold proteins (MSPs) that wrap around the membrane bilayer. We have developed CHARMM-GUI Nanodisc Builder (http://www.charmm-gui.org/input/nanodisc) to facilitate the setup of nanodisc simulation systems by modeling the MSPs with defined size and known structural features. A total of 11 different nanodiscs with a diameter from 80 to 180 Å are made available in both the all-atom CHARMM and two coarse-grained (PACE and Martini) force fields. The usage of the Nanodisc Builder is demonstrated with various simulation systems. The structures and dynamics of proteins and lipids in these systems were analyzed, showing similar behaviors to those from previous all-atom and coarse-grained nanodisc simulations. We expect the Nanodisc Builder to be a convenient and reliable tool for modeling and simulation of nanodisc systems. © 2019 Wiley Periodicals, Inc.

5.
Glycobiology ; 29(4): 320-331, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689864

##### RESUMO

Characterizing glycans and glycoconjugates in the context of three-dimensional structures is important in understanding their biological roles and developing efficient therapeutic agents. Computational modeling and molecular simulation have become an essential tool complementary to experimental methods. Here, we present a computational tool, Glycan Modeler for in silico N-/O-glycosylation of the target protein and generation of carbohydrate-only systems. In our previous study, we developed Glycan Reader, a web-based tool for detecting carbohydrate molecules from a PDB structure and generation of simulation system and input files. As integrated into Glycan Reader in CHARMM-GUI, Glycan Modeler (Glycan Reader & Modeler) enables to generate the structures of glycans and glycoconjugates for given glycan sequences and glycosylation sites using PDB glycan template structures from Glycan Fragment Database (http://glycanstructure.org/fragment-db). Our benchmark tests demonstrate the universal applicability of Glycan Reader & Modeler to various glycan sequences and target proteins. We also investigated the structural properties of modeled glycan structures by running 2-µs molecular dynamics simulations of HIV envelope protein. The simulations show that the modeled glycan structures built by Glycan Reader & Modeler have the similar structural features compared to the ones solved by X-ray crystallography. We also describe the representative examples of glycoconjugate modeling with video demos to illustrate the practical applications of Glycan Reader & Modeler. Glycan Reader & Modeler is freely available at http://charmm-gui.org/input/glycan.

##### Assuntos
Carboidratos/química , Biologia Computacional , Glicoconjugados/química , Polissacarídeos/química , Configuração de Carboidratos , Bases de Dados Factuais
6.
J Chem Theory Comput ; 15(1): 775-786, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30525595

##### RESUMO

Glycolipids (such as glycoglycerolipids, glycosphingolipids, and glycosylphosphatidylinositol) and lipoglycans (such as lipopolysaccharides (LPS), lipooligosaccharides (LOS), mycobacterial lipoarabinomannan, and mycoplasma lipoglycans) are typically found on the surface of cell membranes and play crucial roles in various cellular functions. Characterizing their structure and dynamics at the molecular level is essential to understand their biological roles, but systematic generation of glycolipid and lipoglycan structures is challenging because of great variations in lipid structures and glycan sequences (i.e., carbohydrate types and their linkages). To facilitate the generation of all-atom glycolipid/LPS/LOS structures, we have developed Glycolipid Modeler and LPS Modeler in CHARMM-GUI ( http://www.charmm-gui.org ), a web-based interface that simplifies building of complex biological simulation systems. In addition, we have incorporated these modules into Membrane Builder so that users can readily build a complex symmetric or asymmetric biological membrane system with various glycolipids and LPS/LOS. These tools are expected to be useful in innovative and novel glycolipid/LPS/LOS modeling and simulation research by easing tedious and intricate steps in modeling complex biological systems and shall provide insight into structures, dynamics, and underlying mechanisms of complex glycolipid-/LPS-/LOS-containing biological membrane systems.

##### Assuntos
Glicolipídeos/química , Lipopolissacarídeos/química , Proteínas de Bactérias/química , Antígenos CD59/química , Campylobacter jejuni/química , Membrana Celular/química , Simulação por Computador , Escherichia coli/química , Glicosilfosfatidilinositóis/química , Humanos , Simulação de Dinâmica Molecular , Interface Usuário-Computador
7.
Sci Rep ; 8(1): 16017, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30375453

##### RESUMO

von Willebrand Factor (vWF) is a large multimeric protein that binds to platelets and collagen in blood clotting. vWF A2 domain hosts a proteolytic site for ADAMTS13 (A Disintegrin and Metalloprotease with a ThromboSpondin type 1 motif, member 13) to regulate the size of vWF multimers. This regulation process is highly sensitive to force conditions and protein-glycan interactions as the process occurs in flowing blood. There are two sites on A2 domain (N1515 and N1574) bearing various N-linked glycan structures. In this study, we used molecular dynamics (MD) simulation to study the force-induced unfolding of A2 domain with and without a single N-linked glycan type on each site. The sequential pullout of ß-strands was used to represent a characteristic unfolding sequence of A2. This unfolding sequence varied due to protein-glycan interactions. The force-extension and total energy-extension profiles also show differences in magnitude but similar characteristic shapes between the systems with and without glycans. Systems with N-linked glycans encountered higher energy barriers for full unfolding and even for unfolding up to the point of ADAMTS13 cleavage site exposure. Interestingly, there is not much difference observed for A2 domain structure itself with and without glycans from standard MD simulations, suggesting roles of N-glycans in A2 unfolding through long-ranged protein-glycan interactions.

##### Assuntos
Polissacarídeos/química , Polissacarídeos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Desdobramento de Proteína , Fator de von Willebrand/química , Fator de von Willebrand/metabolismo , Proteína ADAMTS13/química , Proteína ADAMTS13/metabolismo , Humanos , Fenômenos Mecânicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Estabilidade Proteica , Relação Estrutura-Atividade
8.
Proc Natl Acad Sci U S A ; 115(23): 5962-5967, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29784777

##### RESUMO

The phosphoenolpyruvate-dependent phosphotransferase system (PTS) transports sugar into bacteria and phosphorylates the sugar for metabolic consumption. The PTS is important for the survival of bacteria and thus a potential target for antibiotics, but its mechanism of sugar uptake and phosphorylation remains unclear. The PTS is composed of multiple proteins, and the membrane-embedded Enzyme IIC (EIIC) component transports sugars across the membrane. Crystal structures of two members of the glucose superfamily of EIICs, bcChbC and bcMalT, were solved in the inward-facing and outward-facing conformations, and the structures suggest that sugar translocation could be achieved by movement of a structured domain that contains the sugar-binding site. However, different conformations have not been captured on the same transporter to allow precise description of the conformational changes. Here we present a crystal structure of bcMalT trapped in an inward-facing conformation by a mercury ion that bridges two strategically placed cysteine residues. The structure allows direct comparison of the outward- and inward-facing conformations and reveals a large rigid-body motion of the sugar-binding domain and other conformational changes that accompany the rigid-body motion. All-atom molecular dynamics simulations show that the inward-facing structure is stable with or without the cross-linking. The conformational changes were further validated by single-molecule Föster resonance energy transfer (smFRET). Combined, these results establish the elevator-type mechanism of transport in the glucose superfamily of EIIC transporters.

##### Assuntos
Proteínas de Bactérias , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato , Bacillus cereus/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/ultraestrutura , Transporte Biológico , Cisteína/química , Cisteína/metabolismo , Transferência Ressonante de Energia de Fluorescência , Simulação de Dinâmica Molecular , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/química , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/metabolismo , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/ultraestrutura , Fosforilação , Conformação Proteica
9.
Chemosphere ; 188: 697-705, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28934707

##### RESUMO

Wastewater treatment plants (WWTPs) serve as point-source inputs for a variety of nutrients often dominated by nitrogenous compounds as a result of anthropogenic influence. These effluents can impact biogeochemical cycles in freshwater estuaries, influencing microbial communities in both the water and sediment compartments. To assess the impact of point source nutrients, a transect of sediment and pore water samples were collected from 4 locations in the Little River Sub-watershed including locations above and below the Little River Pollution Control Plant (LRPCP). Variation in chemistry and microbial community/gene expression revealed significant influences of the effluent discharge on the adjacent sediments. Phosphorus and sulfur showed high concentrations within plume sediments compared to the reference sediments while nitrate concentrations were low. Increased abundance of denitrifiers Dechloromonas, Dok59 and Thermomonas correlating with increased expression of nitrous-oxide reductase suggests a conversion of N2O to N2 within the LRPCP effluent sediments. This study provides valuable insight into the gene regulation of microbes involved in N metabolism (denitrification, nitrification, and nitrite reduction to ammonia) within the sediment compartment influenced by wastewater effluent.

##### Assuntos
Desnitrificação , Água Doce/microbiologia , Sedimentos Geológicos/química , Nitrificação , Amônia/análise , Amônia/metabolismo , Estuários , Água Doce/química , Regulação Bacteriana da Expressão Gênica , Sedimentos Geológicos/microbiologia , Oxirredutases/metabolismo , Fósforo/análise , Enxofre/análise , Águas Residuárias/química
10.
J Comput Chem ; 38(27): 2354-2363, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28776689

##### RESUMO

A complex cell envelope, composed of a mixture of lipid types including lipopolysaccharides, protects bacteria from the external environment. Clearly, the proteins embedded within the various components of the cell envelope have an intricate relationship with their local environment. Therefore, to obtain meaningful results, molecular simulations need to mimic as far as possible this chemically heterogeneous system. However, setting up such systems for computational studies is far from trivial, and consequently the vast majority of simulations of outer membrane proteins still rely on oversimplified phospholipid membrane models. This work presents an update of CHARMM-GUI Martini Maker for coarse-grained modeling and simulation of complex bacterial membranes with lipopolysaccharides. The qualities of the outer membrane systems generated by Martini Maker are validated by simulating them in bilayer, vesicle, nanodisc, and micelle environments (with and without outer membrane proteins) using the Martini force field. We expect this new feature in Martini Maker to be a useful tool for modeling large, complicated bacterial outer membrane systems in a user-friendly manner. © 2017 Wiley Periodicals, Inc.

##### Assuntos
Bactérias/química , Membrana Celular/química , Lipopolissacarídeos/química , Modelos Químicos , Desenho de Programas de Computador , Proteínas da Membrana Bacteriana Externa/química , Bicamadas Lipídicas/química , Micelas , Simulação de Dinâmica Molecular , Fosfolipídeos/química
11.
Bioinformatics ; 33(19): 3051-3057, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28582506

##### RESUMO

Motivation: Glycans play a central role in many essential biological processes. Glycan Reader was originally developed to simplify the reading of Protein Data Bank (PDB) files containing glycans through the automatic detection and annotation of sugars and glycosidic linkages between sugar units and to proteins, all based on atomic coordinates and connectivity information. Carbohydrates can have various chemical modifications at different positions, making their chemical space much diverse. Unfortunately, current PDB files do not provide exact annotations for most carbohydrate derivatives and more than 50% of PDB glycan chains have at least one carbohydrate derivative that could not be correctly recognized by the original Glycan Reader. Results: Glycan Reader has been improved and now identifies most sugar types and chemical modifications (including various glycolipids) in the PDB, and both PDB and PDBx/mmCIF formats are supported. CHARMM-GUI Glycan Reader is updated to generate the simulation system and input of various glycoconjugates with most sugar types and chemical modifications. It also offers a new functionality to edit the glycan structures through addition/deletion/modification of glycosylation types, sugar types, chemical modifications, glycosidic linkages, and anomeric states. The simulation system and input files can be used for CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Glycan Fragment Database in GlycanStructure.Org is also updated to provide an intuitive glycan sequence search tool for complex glycan structures with various chemical modifications in the PDB. Availability and implementation: http://www.charmm-gui.org/input/glycan and http://www.glycanstructure.org. Contact: wonpil@lehigh.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

##### Assuntos
Bases de Dados de Proteínas , Glicoproteínas/química , Polissacarídeos/química , Carboidratos/química , Açúcares/química
12.
J Comput Chem ; 38(21): 1879-1886, 2017 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-28497616

##### RESUMO

13.
Biophys J ; 112(11): 2249-2252, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28506526

##### RESUMO

Enzyme IIC (EIIC) is a membrane-embedded sugar transport protein that is part of the phosphoenolpyruvate-dependent phosphotransferases. Crystal structures of two members of the glucose EIIC superfamily, bcChbC in the inward-facing conformation and bcMalT in the outward-facing conformation, were previously solved. Comparing the two structures led us to the hypothesis that sugar translocation could be achieved by an elevator-type transport mechanism in which a transport domain binds to the substrate and, through rigid body motions, transports it across the membrane. To test this hypothesis and to obtain more accurate descriptions of alternate conformations of the two proteins, we first performed collective variable-based steered molecular dynamics (CVSMD) simulations starting with the two crystal structures embedded in model lipid bilayers, and steered their transport domain toward their own alternative conformation. Our simulations show that large rigid-body motions of the transport domain (55° in rotation and 8 Å in translation) lead to access of the substrate binding site to the alternate side of the membrane. H-bonding interactions between the sugar and the protein are intact, although the side chains of the binding-site residues were not restrained in the simulation. Pairs of residues in bcMalT that are far apart in the crystal structure become close to each other in the simulated model. Some of these pairs can be cross-linked by a mercury ion when mutated to cysteines, providing further support for the CVSMD-generated model. In addition, bcMalT binds to maltose with similar affinities before and after the cross-linking, suggesting that the binding site is preserved after the conformational change. In combination, these results support an elevator-type transport mechanism in EIIC.

##### Assuntos
Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/metabolismo , Bacillus cereus , Sítios de Ligação , Ligações de Hidrogênio , Bicamadas Lipídicas/química , Maltose/metabolismo , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Simulação de Dinâmica Molecular , Mutação , Fosfatidiletanolaminas/química , Fosfatidilgliceróis/química , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/química , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato/genética
14.
Maxillofac Plast Reconstr Surg ; 39(1): 7, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28303237

##### RESUMO

BACKGROUND: This study was to investigate the effect of biomechanical stimulation on osteoblast differentiation of human periosteal-derived stem cell using the newly developed bioreactor. METHODS: Human periosteal-derived stem cells were harvested from the mandible during the extraction of an impacted third molar. Using the new bioreactor, 4% cyclic equibiaxial tension force (0.5 Hz) was applied for 2 and 8 h on the stem cells and cultured for 3, 7, and 14 days on the osteogenic medium. Biochemical changes of the osteoblasts after the biomechanical stimulation were investigated. No treatment group was referred to as control group. RESULTS: Alkaline phosphatase (ALP) activity and ALP messenger RNA (mRNA) expression level were higher in the strain group than those in the control group. The osteocalcin and osteonectin mRNA expressions were higher in the strain group compared to those in the control group on days 7 and 14. The vascular endothelial growth factor (VEGF) mRNA expression was higher in the strain group in comparison to that in the control group. Concentration of alizarin red S corresponding to calcium content was higher in the strain group than in the control group. CONCLUSIONS: The study suggests that cyclic tension force could influence the osteoblast differentiation of periosteal-derived stem cells under optimal stimulation condition and the force could be applicable for tissue engineering.

15.
J Comput Chem ; 38(15): 1114-1124, 2017 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-27862047

##### RESUMO

CHARMM-GUI, http://www.charmm-gui.org, is a web-based graphical user interface that prepares complex biomolecular systems for molecular simulations. CHARMM-GUI creates input files for a number of programs including CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Since its original development in 2006, CHARMM-GUI has been widely adopted for various purposes and now contains a number of different modules designed to set up a broad range of simulations: (1) PDB Reader & Manipulator, Glycan Reader, and Ligand Reader & Modeler for reading and modifying molecules; (2) Quick MD Simulator, Membrane Builder, Nanodisc Builder, HMMM Builder, Monolayer Builder, Micelle Builder, and Hex Phase Builder for building all-atom simulation systems in various environments; (3) PACE CG Builder and Martini Maker for building coarse-grained simulation systems; (4) DEER Facilitator and MDFF/xMDFF Utilizer for experimentally guided simulations; (5) Implicit Solvent Modeler, PBEQ-Solver, and GCMC/BD Ion Simulator for implicit solvent related calculations; (6) Ligand Binder for ligand solvation and binding free energy simulations; and (7) Drude Prepper for preparation of simulations with the CHARMM Drude polarizable force field. Recently, new modules have been integrated into CHARMM-GUI, such as Glycolipid Modeler for generation of various glycolipid structures, and LPS Modeler for generation of lipopolysaccharide structures from various Gram-negative bacteria. These new features together with existing modules are expected to facilitate advanced molecular modeling and simulation thereby leading to an improved understanding of the structure and dynamics of complex biomolecular systems. Here, we briefly review these capabilities and discuss potential future directions in the CHARMM-GUI development project. © 2016 Wiley Periodicals, Inc.

##### Assuntos
Membrana Celular/química , Glicoconjugados/química , Simulação de Dinâmica Molecular , Proteínas/química , Software , Animais , Gráficos por Computador , Bases de Dados de Proteínas , Espectroscopia de Ressonância de Spin Eletrônica , Bactérias Gram-Negativas/química , Humanos , Ligantes , Solventes/química , Interface Usuário-Computador
16.
J Phys Chem B ; 121(15): 3718-3723, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-27936734

##### RESUMO

X-ray crystallography and cryo-electron microscopy are two popular methods for the structure determination of biological molecules. Atomic structures are derived through the fitting and refinement of an initial model into electron density maps constructed by both experiments. Two computational approaches, MDFF and xMDFF, have been developed to facilitate this process by integrating the experimental data with molecular dynamics simulation. However, the setup of an MDFF/xMDFF simulation requires knowledge of both experimental and computational methods, which is not straightforward for nonexpert users. In addition, sometimes it is desirable to include realistic environments, such as explicit solvent and lipid bilayers during the simulation, which poses another challenge even for expert users. To alleviate these difficulties, we have developed MDFF/xMDFF Utilizer in CHARMM-GUI that helps users to set up an MDFF/xMDFF simulation. The capability of MDFF/xMDFF Utilizer is greatly enhanced by integration with other CHARMM-GUI modules, including protein structure manipulation, a diverse set of lipid types, and all-atom CHARMM and coarse-grained PACE force fields. With this integration, various simulation environments are available for MDFF Utilizer (vacuum, implicit/explicit solvent, and bilayers) and xMDFF Utilizer (vacuum and solution). In this work, three examples are shown to demonstrate the usage of MDFF/xMDFF Utilizer.

##### Assuntos
Simulação de Dinâmica Molecular , Interface Usuário-Computador , Microscopia Crioeletrônica , Cristalografia por Raios X , Bicamadas Lipídicas/química , Lipídeos/química , Solventes/química
17.
Structure ; 24(6): 956-64, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27161976

##### RESUMO

The phosphoenolpyruvate:carbohydrate phosphotransferase systems are found in bacteria, where they play central roles in sugar uptake and regulation of cellular uptake processes. Little is known about how the membrane-embedded components (EIICs) selectively mediate the passage of carbohydrates across the membrane. Here we report the functional characterization and 2.55-Å resolution structure of a maltose transporter, bcMalT, belonging to the glucose superfamily of EIIC transporters. bcMalT crystallized in an outward-facing occluded conformation, in contrast to the structure of another glucose superfamily EIIC, bcChbC, which crystallized in an inward-facing occluded conformation. The structures differ in the position of a structurally conserved substrate-binding domain that is suggested to play a central role in sugar transport. In addition, molecular dynamics simulations suggest a potential pathway for substrate entry from the periplasm into the bcMalT substrate-binding site. These results provide a mechanistic framework for understanding substrate recognition and translocation for the glucose superfamily EIIC transporters.

##### Assuntos
Membrana Celular/metabolismo , Glucose/metabolismo , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Metabolismo dos Carboidratos , Cristalografia por Raios X , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , Transporte Proteico , Especificidade por Substrato
18.
J Chem Theory Comput ; 12(1): 405-13, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26631602

##### RESUMO

Proper treatment of nonbonded interactions is essential for the accuracy of molecular dynamics (MD) simulations, especially in studies of lipid bilayers. The use of the CHARMM36 force field (C36 FF) in different MD simulation programs can result in disagreements with published simulations performed with CHARMM due to differences in the protocols used to treat the long-range and 1-4 nonbonded interactions. In this study, we systematically test the use of the C36 lipid FF in NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM. A wide range of Lennard-Jones (LJ) cutoff schemes and integrator algorithms were tested to find the optimal simulation protocol to best match bilayer properties of six lipids with varying acyl chain saturation and head groups. MD simulations of a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer were used to obtain the optimal protocol for each program. MD simulations with all programs were found to reasonably match the DPPC bilayer properties (surface area per lipid, chain order parameters, and area compressibility modulus) obtained using the standard protocol used in CHARMM as well as from experiments. The optimal simulation protocol was then applied to the other five lipid simulations and resulted in excellent agreement between results from most simulation programs as well as with experimental data. AMBER compared least favorably with the expected membrane properties, which appears to be due to its use of the hard-truncation in the LJ potential versus a force-based switching function used to smooth the LJ potential as it approaches the cutoff distance. The optimal simulation protocol for each program has been implemented in CHARMM-GUI. This protocol is expected to be applicable to the remainder of the additive C36 FF including the proteins, nucleic acids, carbohydrates, and small molecules.

##### Assuntos
Bicamadas Lipídicas/metabolismo , Simulação de Dinâmica Molecular , 1,2-Dipalmitoilfosfatidilcolina/química , Bicamadas Lipídicas/química , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Fosfatidilserinas/química , Esfingomielinas/química
19.
J Chem Theory Comput ; 11(9): 4486-94, 2015 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-26575938

##### RESUMO

Coarse-grained simulations are widely used to study large biological systems. Nonetheless, building such simulation systems becomes nontrivial, especially when membranes with various lipid types are involved. Taking advantage of the frameworks in all-atom CHARMM-GUI modules, we have developed CHARMM-GUI Martini Maker for building solution, micelle, bilayer, and vesicle systems as well as systems with randomly distributed lipids using the Martini force field. Martini Maker supports 82 lipid types and different flavors of the Martini force field, including polar and nonpolar Martini, Dry Martini, and ElNeDyn (an elastic network model for proteins). The qualities of the systems generated by Martini Maker are validated by simulations of various examples involving proteins and lipids. We expect Martini Maker to be a useful tool for modeling large, complicated biomolecular systems in a user-friendly way.

##### Assuntos
Gráficos por Computador , Lipídeos/química , Simulação de Dinâmica Molecular , Proteínas/química , Micelas , Software
20.
Biophys J ; 109(10): 2012-22, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26588561

##### RESUMO

Slow diffusion of the lipids in conventional all-atom simulations of membrane systems makes it difficult to sample large rearrangements of lipids and protein-lipid interactions. Recently, Tajkhorshid and co-workers developed the highly mobile membrane-mimetic (HMMM) model with accelerated lipid motion by replacing the lipid tails with small organic molecules. The HMMM model provides accelerated lipid diffusion by one to two orders of magnitude, and is particularly useful in studying membrane-protein associations. However, building an HMMM simulation system is not easy, as it requires sophisticated treatment of the lipid tails. In this study, we have developed CHARMM-GUI HMMM Builder (http://www.charmm-gui.org/input/hmmm) to provide users with ready-to-go input files for simulating HMMM membrane systems with/without proteins. Various lipid-only and protein-lipid systems are simulated to validate the qualities of the systems generated by HMMM Builder with focus on the basic properties and advantages of the HMMM model. HMMM Builder supports all lipid types available in CHARMM-GUI and also provides a module to convert back and forth between an HMMM membrane and a full-length membrane. We expect HMMM Builder to be a useful tool in studying membrane systems with enhanced lipid diffusion.

##### Assuntos
Membrana Celular/química , Simulação de Dinâmica Molecular , Software , Sequência de Aminoácidos , Lipídeos de Membrana/química , Proteínas de Membrana/química , Dados de Sequência Molecular