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1.
Front Mol Biosci ; 8: 699222, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34268334

RESUMO

Multicomponent transporters are used by bacteria to transport a wide range of nutrients. These systems use a substrate-binding protein to bind the nutrient with high affinity and then deliver it to a membrane-bound transporter for uptake. Nutrient uptake pathways are linked to the colonisation potential and pathogenicity of bacteria in humans and may be candidates for antimicrobial targeting. Here we review current research into bacterial multicomponent transport systems, with an emphasis on the interaction at the membrane, as well as new perspectives on the role of lipids and higher oligomers in these complex systems.

2.
J Chem Phys ; 154(15): 154105, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33887942

RESUMO

Cyclodextrins have a diverse range of applications, including as supramolecular hosts, as enzyme active-site analogs, in improving drug solubility and delivery, and in molecular selection. We have investigated their ability to form stable complexes with bullvalenes, unusual organic cage molecules that spontaneously interconvert between numerous degenerate isomers. The shape-shifting nature of substituted bullvalenes raises the potential for dynamic adaptive binding to biological targets. We tested whether ß- and γ-cyclodextrins can capture particular bullvalene isomers and whether the preferred binding mode(s) differ between isomers. We first applied our computational host-guest interaction potential energy profiling to determine the best binding mode(s) of unsubstituted bullvalene and each isomer of methylenehydroxybullvalene to ß- and γ-cyclodextrin. Subsequent molecular dynamics simulations of the predicted host-guest complexes showed that while unsubstituted bullvalene has a single, albeit ill-defined, binding mode with either cyclodextrin, each isomer of methylenehydroxybullvalene has two possible modes of binding to ß-cyclodextrin but only a single, nebulous mode of binding to γ-cyclodextrin. Experimental determination of the binding free energy of each methylenehydroxybullvalene-cyclodextrin complex showed that methylenehydroxybullvalene is more likely to bind to ß-cyclodextrin than to γ-cyclodextrin, despite its smaller cavity. Together, our results suggest that ß-cyclodextrin, but not γ-cyclodextrin, shows promise for conformational capture of mono-substituted bullvalenes. More broadly, our computational pipeline should prove useful for rapid characterization of cyclodextrin host-guest complexes, avoiding the need for costly synthesis of guest molecules that are unlikely to bind stably, as well as providing detailed atomic-level insight into the nature of complexation.


Assuntos
Hidrocarbonetos Alicíclicos/química , beta-Ciclodextrinas/química , gama-Ciclodextrinas/química , Conformação Molecular , Simulação de Dinâmica Molecular , Termodinâmica
3.
ACS Omega ; 6(1): 388-400, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33458490

RESUMO

Antimicrobial peptides (AMPs) are a potential solution to the increasing threat of antibiotic resistance, but successful design of active but nontoxic AMPs requires understanding their mechanism of action. Molecular dynamics (MD) simulations can provide atomic-level information regarding how AMPs interact with the cell membrane. Here, we have used MD simulations to study two linear analogs of battacin, a naturally occurring cyclic, lipidated, nonribosomal AMP. Like battacin, these analogs are active against Gram-negative multidrug resistant and Gram-positive bacteria, but they are less toxic than battacin. Our simulations show that this activity depends upon a combination of positively charged and hydrophobic moieties. Favorable interactions with negatively charged membrane lipid head groups drive association with the membrane and insertion of hydrophobic residues, and the N-terminal lipid anchors the peptides to the membrane surface. Both effects are required for stable membrane binding.

4.
Biochem Soc Trans ; 48(4): 1707-1724, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32756904

RESUMO

Proteins are dynamic molecules that can transition between a potentially wide range of structures comprising their conformational ensemble. The nature of these conformations and their relative probabilities are described by a high-dimensional free energy landscape. While computer simulation techniques such as molecular dynamics simulations allow characterisation of the metastable conformational states and the transitions between them, and thus free energy landscapes, to be characterised, the barriers between states can be high, precluding efficient sampling without substantial computational resources. Over the past decades, a dizzying array of methods have emerged for enhancing conformational sampling, and for projecting the free energy landscape onto a reduced set of dimensions that allow conformational states to be distinguished, known as collective variables (CVs), along which sampling may be directed. Here, a brief description of what biomolecular simulation entails is followed by a more detailed exposition of the nature of CVs and methods for determining these, and, lastly, an overview of the myriad different approaches for enhancing conformational sampling, most of which rely upon CVs, including new advances in both CV determination and conformational sampling due to machine learning.


Assuntos
Biologia Computacional , Proteínas/química , Simulação de Dinâmica Molecular , Conformação Proteica
5.
Mol Biol Evol ; 37(9): 2711-2726, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302382

RESUMO

For evaluating the deepest evolutionary relationships among proteins, sequence similarity is too low for application of sequence-based homology search or phylogenetic methods. In such cases, comparison of protein structures, which are often better conserved than sequences, may provide an alternative means of uncovering deep evolutionary signal. Although major protein structure databases such as SCOP and CATH hierarchically group protein structures, they do not describe the specific evolutionary relationships within a hierarchical level. Structural phylogenies have the potential to fill this gap. However, it is difficult to assess evolutionary relationships derived from structural phylogenies without some means of assessing confidence in such trees. We therefore address two shortcomings in the application of structural data to deep phylogeny. First, we examine whether phylogenies derived from pairwise structural comparisons are sensitive to differences in protein length and shape. We find that structural phylogenetics is best employed where structures have very similar lengths, and that shape fluctuations generated during molecular dynamics simulations impact pairwise comparisons, but not so drastically as to eliminate evolutionary signal. Second, we address the absence of statistical support for structural phylogeny. We present a method for assessing confidence in a structural phylogeny using shape fluctuations generated via molecular dynamics or Monte Carlo simulations of proteins. Our approach will aid the evolutionary reconstruction of relationships across structurally defined protein superfamilies. With the Protein Data Bank now containing in excess of 158,000 entries (December 2019), we predict that structural phylogenetics will become a useful tool for ordering the protein universe.


Assuntos
Evolução Molecular , Técnicas Genéticas , Filogenia , Elementos Estruturais de Proteínas/genética , Simulação de Dinâmica Molecular , Método de Monte Carlo
6.
J Biol Chem ; 295(13): 4181-4193, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32071083

RESUMO

Strigolactones (SLs) are terpenoid-derived plant hormones that regulate various developmental processes, particularly shoot branching, root development, and leaf senescence. The SL receptor has an unusual mode of action. Upon binding SL, it hydrolyzes the hormone, and then covalently binds one of the hydrolytic products. These initial events enable the SL receptor DAD2 (in petunia) to interact with the F-box protein PhMAX2A of the Skp-Cullin-F-box (SCF) complex and/or a repressor of SL signaling, PhD53A. However, it remains unclear how binding and hydrolysis structurally alters the SL receptor to enable its engagement with signaling partners. Here, we used mutagenesis to alter DAD2 and affect SL hydrolysis or DAD2's ability to interact with its signaling partners. We identified three DAD2 variants whose hydrolytic activity had been separated from the receptor's interactions with PhMAX2A or PhD53A. Two variants, DAD2N242I and DAD2F135A, having substitutions in the core α/ß hydrolase-fold domain and the hairpin, exhibited hormone-independent interactions with PhMAX2A and PhD53A, respectively. Conversely, the DAD2D166A variant could not interact with PhMAX2A in the presence of SL, but its interaction with PhD53A remained unaffected. Structural analyses of DAD2N242I and DAD2D166A revealed only small differences compared with the structure of the WT receptor. Results of molecular dynamics simulations of the DAD2N242I structure suggested that increased flexibility is a likely cause for its SL-independent interaction with PhMAX2A. Our results suggest that PhMAX2A and PhD53A have distinct binding sites on the SL receptor and that its flexibility is a major determinant of its interactions with these two downstream regulators.


Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Lactonas/química , Petunia/química , Reguladores de Crescimento de Plantas/genética , Proteínas de Plantas/química , Proteínas F-Box/química , Proteínas F-Box/genética , Regulação da Expressão Gênica de Plantas/genética , Hidrolases/química , Hidrolases/genética , Petunia/genética , Reguladores de Crescimento de Plantas/química , Proteínas de Plantas/genética , Ligação Proteica/genética , Proteínas Ligases SKP Culina F-Box/química , Proteínas Ligases SKP Culina F-Box/genética , Transdução de Sinais/genética
7.
Methods Mol Biol ; 2073: 311-327, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31612449

RESUMO

Molecular dynamics simulations allow the conformational motion of a molecule such as a protein to be followed over time at atomic-level detail. Several choices need to be made prior to running a simulation, including the software, which molecules to include in the simulation, and the force field used to describe their behavior. Guidance on making these choices and other important aspects of running MD simulations is outlined here.


Assuntos
Simulação de Dinâmica Molecular , Proteínas/química , Biologia Computacional , Proteínas/ultraestrutura , Software
8.
Protein Sci ; 29(1): 157-168, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622516

RESUMO

A key learning outcome for undergraduate biochemistry classes is a thorough understanding of the principles of protein structure. Traditional approaches to teaching this material, which include two-dimensional (2D) images on paper, physical molecular modeling kits, and projections of 3D structures into 2D, are unable to fully capture the dynamic 3D nature of proteins. We have built a virtual reality application, Peppy, aimed at facilitating teaching of the principles of protein secondary structure. Rather than attempt to model molecules with the same fidelity to the underlying physical chemistry as existing, research-oriented molecular modelling approaches, we took the more straightforward approach of harnessing the Unity video game physics engine. Indeed, the simplicity and limitations of our model are strengths in a teaching context, provoking questions and thus deeper understanding. Peppy allows exploration of the relative effects of hydrogen bonding (and electrostatic interactions more generally), backbone φ/ψ angles, basic chemical structure, and steric effects on a polypeptide structure in an accessible format that is novel, dynamic, and fun to use. Apart from describing the implementation and use of Peppy, we discuss the outcomes of deploying Peppy in undergraduate biochemistry courses.


Assuntos
Bioquímica/educação , Peptídeos/química , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Secundária de Proteína , Interface Usuário-Computador , Jogos de Vídeo , Realidade Virtual
9.
Chem Sci ; 11(22): 5759-5765, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34094080

RESUMO

We herein report the synthesis and biological and computational evaluation of 12 linear analogues of the cyclic lipopeptide battacin, enabled by Cysteine Lipidation on a Peptide or Amino Acid (CLipPA) technology. Several of the novel "CLipP"ed lipopeptides exhibited low micromolar MICs and MBCs against both Gram-negative and Gram-positive bacteria. The mechanism of action was then simulated with the MIC data using computational methods.

10.
Methods Mol Biol ; 2003: 1-30, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218611

RESUMO

Lipid membranes play a crucial role in living systems by compartmentalizing biological processes and forming a barrier between these processes and the environment. Naturally, a large apparatus of biomolecules is responsible for construction, maintenance, transport, and degradation of these lipid barriers. Additional classes of biomolecules are tasked with transport of specific substances or transduction of signals from the environment across lipid membranes. In this article, we intend to describe a set of techniques that enable one to build accurate models of lipid systems and their associated proteins, and to simulate their dynamics over a variety of time and length scales. We discuss the methods and challenges that allow us to derive structural, mechanistic, and thermodynamic information from these models. We also show how these models have recently been applied in research to study some of the most complex lipid-protein systems to date, including bacterial and viral envelopes, neuronal membranes, and mammalian signaling systems.


Assuntos
Bicamadas Lipídicas/metabolismo , Lipídeos de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Animais , Membrana Celular/metabolismo , Simulação de Dinâmica Molecular , Transdução de Sinais/fisiologia , Termodinâmica
11.
Front Chem ; 7: 400, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231634

RESUMO

Molecular simulations allow investigation of the structure, dynamics and thermodynamics of molecules at an atomic level of detail, and as such, are becoming increasingly important across many areas of science. As the range of applications increases, so does the variety of molecules. Simulation of a new type of molecule requires generation of parameters that result in accurate representation of the behavior of that molecule, and, in most cases, are compatible with existing parameter sets. While many automated parametrization methods exist, they are in general not well suited to large and conformationally dynamic molecules. We present here a method for automated assignment of parameters for large, novel biomolecules, and demonstrate its usage for peptides of varying degrees of complexity. Our method uses a graph theoretic representation to facilitate matching of the target molecule to molecular fragments for which reliable parameters are available. It requires minimal user input and creates parameter files compatible with the widely-used GROMACS simulation software.

12.
J Biol Chem ; 294(22): 8806-8818, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-30996005

RESUMO

Aß1-42 is involved in Alzheimer's disease (AD) pathogenesis and is prone to glycation, an irreversible process where proteins accumulate advanced glycated end products (AGEs). N ϵ-(Carboxyethyl)lysine (CEL) is a common AGE associated with AD patients and occurs at either Lys-16 or Lys-28 of Aß1-42. Methyglyoxal is commonly used for the unspecific glycation of Aß1-42, which results in a complex mixture of AGE-modified peptides and makes interpretation of a causative AGE at a specific amino acid residue difficult. We address this issue by chemically synthesizing defined CEL modifications on Aß1-42 at Lys-16 (Aß-CEL16), Lys-28 (Aß-CEL28), and Lys-16 and -28 (Aß-CEL16&28). We demonstrated that double-CEL glycations at Lys-16 and Lys-28 of Aß1-42 had the most profound impact on the ability to form amyloid fibrils. In silico predictions indicated that Aß-CEL16&28 had a substantial decrease in free energy change, which contributes to fibril destabilization, and a increased aggregation rate. Single-CEL glycations at Lys-28 of Aß1-42 had the least impact on fibril formation, whereas CEL glycations at Lys-16 of Aß1-42 delayed fibril formation. We also tested these peptides for neuronal toxicity and mitochondrial function on a retinoic acid-differentiated SH-SY5Y human neuroblastoma cell line (RA-differentiated SH-SY5Y). Only Aß-CEL16 and Aß-CEL28 were neurotoxic, possibly through a nonmitochondrial pathway, whereas Aß-CEL16&28 showed no neurotoxicity. Interestingly, Aß-CEL16&28 had depolarized the mitochondrial membrane potential, whereas Aß-CEL16 had increased mitochondrial respiration at complex II. These results may indicate mitophagy or an alternate route of metabolism, respectively. Therefore, our results provides insight into potential therapeutic approaches against neurotoxic CEL-glycated Aß1-42.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/síntese química , Peptídeos beta-Amiloides/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Glicosilação , Humanos , Lisina/análogos & derivados , Lisina/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/toxicidade , Agregados Proteicos , Conformação Proteica em Folha beta , Estabilidade Proteica , Oxigênio Singlete/metabolismo
13.
J Cheminform ; 11(1): 18, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30840171

RESUMO

Bond orders and formal charges are fundamental chemical descriptors. In cheminformatic applications it is necessary to be able to assign these properties to a given molecular structure automatically, given minimal input information. Here we describe a method for determining the bond order and formal charge assignments from only the atom types and connectivity. Our method utilises a graph theoretical description of electron positions. Each electron position assignment is scored according to lookup tables of atomic and bond dissociation energies derived from quantum chemical calculations. We tested three different optimisation methods-local optimisation, an A* pathfinding method, and an FPT optimisation method utilising tree decompositions-for finding the best electron position assignment, from which the bond orders and formal charges are extracted. We show that our method can assign bond orders and formal charges at a high degree of accuracy across a wide range of molecules from two different databases, and that the FPT algorithm provides the best combination of speed and accuracy.

14.
Chem Asian J ; 14(8): 1221-1229, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30663846

RESUMO

The development of luminescent surfaces is an active area of supramolecular chemistry, particularly for the development of new sensing platforms. One particularly useful surface deposition method is the Langmuir-Blodgett technique where organic amphiphilic fluorophores (e.g. 1,8-naphthalimides) can form ordered monolayers at an air-water interface before being deposited onto solid supports. The ability to simulate monolayer formation and consequently develop predictability over film formation would allow for significant advances in the luminescent materials field where synthesis might be directed by simulation data. Here, we compare pressure-area isotherms of N-(octadecyl)-1,8-naphthalimide determined experimentally, using the Langmuir-Blodgett technique, and computationally, using three different simulation techniques. We find that all three simulation techniques are able to describe the liquid-condensed/liquid-expanded region of the isotherm, and that the isotherms are highly similar in this region, although the NγT ensemble performs best. Experimental isotherms showed film formation properties that align with the simulation data, suggesting that simulations are a viable means to direct synthesis. Investigation of the underlying structural details disclosed by the simulations reveals the compression-induced ordering at atomic-level detail, which will allow prediction of how functionalisation of the naphthalimides will alter the monolayer compression and mounting process.

15.
Structure ; 27(2): 371-380.e3, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30528597

RESUMO

Prediction and characterization of how transiently membrane-bound signaling proteins interact with the cell membrane is important for understanding and controlling cellular signal transduction networks. Existing computational methods rely on approximate descriptions of the components of the system or their interactions, and thus are unable to identify residue- or lipid-specific contributions. Our rotational interaction energy profiling method allows rapid evaluation of an electrostatically optimal orientation of a protein for membrane association, as well as the residues or lipid species responsible for its favorability. This enables prediction of which aspects of the protein-membrane interaction to target experimentally, and thus the development of testable hypotheses, as well as providing efficient seeding of molecular dynamics simulations to further characterize the protein-membrane interaction. We illustrate our method on two proteins of the PIP3 cell signaling system, PTEN and PI3Kα.


Assuntos
Biologia Computacional/métodos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Aminoácidos/metabolismo , Sítios de Ligação , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , PTEN Fosfo-Hidrolase/química , PTEN Fosfo-Hidrolase/metabolismo , Ligação Proteica , Transdução de Sinais
16.
Front Chem ; 6: 233, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30023356

RESUMO

Mammalian cell surfaces are decorated with complex glycoconjugates that terminate with negatively charged sialic acids. Commensal and pathogenic bacteria can use host-derived sialic acids for a competitive advantage, but require a functional sialic acid transporter to import the sugar into the cell. This work investigates the sodium sialic acid symporter (SiaT) from Staphylococcus aureus (SaSiaT). We demonstrate that SaSiaT rescues an Escherichia coli strain lacking its endogenous sialic acid transporter when grown on the sialic acids N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc). We then develop an expression, purification and detergent solubilization system for SaSiaT and demonstrate that the protein is largely monodisperse in solution with a stable monomeric oligomeric state. Binding studies reveal that SaSiaT has a higher affinity for Neu5Gc over Neu5Ac, which was unexpected and is not seen in another SiaT homolog. We develop a homology model and use comparative sequence analyses to identify substitutions in the substrate-binding site of SaSiaT that may explain the altered specificity. SaSiaT is shown to be electrogenic, and transport is dependent upon more than one Na+ ion for every sialic acid molecule. A functional sialic acid transporter is essential for the uptake and utilization of sialic acid in a range of pathogenic bacteria, and developing new inhibitors that target these transporters is a valid mechanism for inhibiting bacterial growth. By demonstrating a route to functional recombinant SaSiaT, and developing the in vivo and in vitro assay systems, our work underpins the design of inhibitors to this transporter.

17.
Eur Biophys J ; 47(7): 739-750, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29663020

RESUMO

Milk components, such as proteins and lipids, have different physicochemical properties depending upon the mammalian species from which they come. Understanding the different responses of these milks to digestion, processing, and differences in their immunogenicity requires detailed knowledge of these physicochemical properties. Here we report on the oligomeric state of ß-lactoglobulin from caprine milk, the most abundant protein present in the whey fraction. At pH 2.5 caprine ß-lactoglobulin is predominantly monomeric, whereas bovine ß-lactoglobulin exists in a monomer-dimer equilibrium at the same protein concentrations. This behaviour was also observed in molecular dynamics simulations and can be rationalised in terms of the amino acid substitutions present between caprine and bovine ß-lactoglobulin that result in a greater positive charge on each subunit of caprine ß-lactoglobulin at low pH. The denaturation of ß-lactoglobulin when milk is heat-treated contributes to the fouling of heat-exchange surfaces, reducing yields and increasing cleaning costs. The bovine and caprine orthologues of ß-lactoglobulin display different responses to thermal treatment, with caprine ß-lactoglobulin precipitating at higher pH values than bovine ß-lactoglobulin (pH 7.1 compared to pH 5.6) that are closer to the natural pH of these milks (pH 6.7). This property of caprine ß-lactoglobulin likely contributes to the reduced heat stability of caprine milk compared to bovine milk at its natural pH.


Assuntos
Lactoglobulinas/química , Agregados Proteicos , Desnaturação Proteica , Temperatura , Sequência de Aminoácidos , Animais , Bovinos , Cabras , Simulação de Dinâmica Molecular , Conformação Proteica
18.
J Chem Theory Comput ; 13(11): 5683-5696, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-28876925

RESUMO

For molecular dynamics simulations of biological membrane systems to live up to the potential of providing accurate atomic level detail into membrane properties and functions, it is essential that the force fields used to model such systems are as accurate as possible. One membrane property that is often used to assess force field accuracy is the carbon-hydrogen (or carbon-deuterium) order parameters of the lipid tails, which can be accurately measured using experimental NMR techniques. There are a variety of analysis tools available to calculate these order parameters from simulations and it is essential that these computational tools work correctly to ensure the accurate assessment of the simulation force fields. In this work we compare many of these computational tools for calculating the order parameters of POPC membranes. While tools that work on all-atom systems and tools that work on saturated lipid tails in general work extremely well, we demonstrate that the majority of the tested tools that calculate the order parameters for unsaturated united-atom lipid tails do so incorrectly. We identify tools that do perform accurate calculations and include one such program with this work, enabling rapid and accurate calculation of united-atom lipid order parameters. Furthermore, we discuss cases in which it is nontrivial to appropriately predict the unsaturated carbon order parameters in united-atom systems. Finally, we examine order parameter splitting for carbon 2 in sn-2 lipid chains, demonstrating substantial deviations from experimental values in several all-atom and united-atom lipid force fields.


Assuntos
Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Modelos Biológicos
19.
Prog Biophys Mol Biol ; 128: 133-141, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28223155

RESUMO

Residual dipolar couplings (RDCs), unlike most other types of NMR observables, provide orientational information, reporting on the alignment of inter-spin vectors (ISVs) relative to the magnetic field. A great challenge in using experimental RDCs to restrain molecular dynamics (MD) simulations is how to represent this alignment. An alignment tensor is often used to parameterise the contribution of molecular alignment to the angular dependence of RDCs. All ISVs that share the same tensor have fixed relative alignment, i.e. if just one tensor is used, the molecule is internally rigid. Here we propose and illustrate a method for subdividing molecules into individually aligned blocks during MD simulations restrained to fit RDCs. This allows the relative orientation of each block to vary during the simulation, which in turn ensures that the internal structure of each block is more realistically reproduced.


Assuntos
Simulação de Dinâmica Molecular , Peptídeos/química , Alinhamento de Sequência , Domínios Proteicos
20.
Curr Opin Struct Biol ; 43: 79-87, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27940377

RESUMO

In their biological environment, proteins are dynamic molecules, necessitating an ensemble structural description. Molecular dynamics simulations and solution-state experiments provide complimentary information in the form of atomically detailed coordinates and averaged or distributions of structural properties or related quantities. Recently, increases in the temporal and spatial scale of conformational sampling and comparison of the more diverse conformational ensembles thus generated have revealed the importance of sampling rare events. Excitingly, new methods based on maximum entropy and Bayesian inference are promising to provide a statistically sound mechanism for combining experimental data with molecular dynamics simulations.


Assuntos
Simulação de Dinâmica Molecular , Proteínas/química , Teorema de Bayes , Entropia , Conformação Proteica , Proteínas/metabolismo
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