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1.
Molecules ; 26(7)2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33917637

RESUMEN

The majority of snacks expanded by extrusion (SEE) are made with vegetable sources, to improve their nutritional content; it has been proposed to incorporate squid (Dosidicus gigas), due to its high protein content, low price and high availability. However, the interaction of proteins of animal origin with starch during extrusion causes negative effects on the sensory properties of SEE, so it is necessary to know the type of protein-carbohydrate interactions and their effect on these properties. The objective of this research was to study the interaction of proteins and carbohydrates of SEE elaborated with squid mantle, potato and corn. The nutritional composition and protein digestibility were evaluated, Fourier transform infrared (FTIR) and Differential Scanning Calorimetry (DSC) were used to study the formation of protein-starch complexes and the possible regions responsible for their interactions. The SEE had a high protein content (40-85%) and biological value (>93%). The melting temperature (Tm) was found between 145 and 225 °C; the Tm values in extruded samples are directly proportional to the squid content. The extrusion process reduced the amine groups I and II responsible for the protein-protein interaction and increased the O-glucosidic bonds, so these bonds could be responsible for the protein-carbohydrate interactions.


Asunto(s)
Rastreo Diferencial de Calorimetría , Decapodiformes/química , Proteínas/química , Bocadillos , Solanum tuberosum/química , Almidón/química , Animales , Espectroscopía Infrarroja por Transformada de Fourier
2.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809541

RESUMEN

Liquid-liquid phase separation (LLPS) is a molecular process that leads to the formation of membraneless organelles, representing functionally specialized liquid-like cellular condensates formed by proteins and nucleic acids. Integrating the data on LLPS-associated proteins from dedicated databases revealed only modest agreement between them and yielded a high-confidence dataset of 89 human LLPS drivers. Analysis of the supporting evidence for our dataset uncovered a systematic and potentially concerning difference between protein concentrations used in a good fraction of the in vitro LLPS experiments, a key parameter that governs the phase behavior, and the proteomics-derived cellular abundance levels of the corresponding proteins. Closer scrutiny of the underlying experimental data enabled us to offer a sound rationale for this systematic difference, which draws on our current understanding of the cellular organization of the proteome and the LLPS process. In support of this rationale, we find that genes coding for our human LLPS drivers tend to be dosage-sensitive, suggesting that their cellular availability is tightly regulated to preserve their functional role in direct or indirect relation to condensate formation. Our analysis offers guideposts for increasing agreement between in vitro and in vivo studies, probing the roles of proteins in LLPS.


Asunto(s)
Dosificación de Gen , Genes , Transición de Fase , Proteínas/química , Bases de Datos Factuales , Humanos , Anotación de Secuencia Molecular , Orgánulos , Proteoma/metabolismo
3.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806656

RESUMEN

Ligand-protein binding is responsible for the vast majority of bio-molecular functions. Most experimental techniques examine the most populated ligand-bound state. The determination of less populated, intermediate, and transient bound states is experimentally challenging. However, hidden bound states are also important because these can strongly influence ligand binding and unbinding processes. Here, we explored the use of a classical optical spectroscopic technique, red-edge excitation shift spectroscopy (REES) to determine the number, population, and energetics associated with ligand-bound states in protein-ligand complexes. We describe a statistical mechanical model of a two-level fluorescent ligand located amongst a finite number of discrete protein microstates. We relate the progressive emission red shift with red-edge excitation to thermodynamic parameters underlying the protein-ligand free energy landscape and to photo-physical parameters relating to the fluorescent ligand. We applied the theoretical model to published red-edge excitation shift data from small molecule inhibitor-kinase complexes. The derived thermodynamic parameters allowed dissection of the energetic contribution of intermediate bound states to inhibitor-kinase interactions.


Asunto(s)
Proteínas/química , Espectrometría de Fluorescencia/métodos , Polarización de Fluorescencia/métodos , Colorantes Fluorescentes/química , Ligandos , Bibliotecas de Moléculas Pequeñas/química , Termodinámica
4.
Nat Commun ; 12(1): 2090, 2021 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-33828103

RESUMEN

An increasing number of density maps of biological macromolecules have been determined by cryo-electron microscopy (cryo-EM) and stored in the public database, EMDB. To interpret the structural information contained in EM density maps, alignment of maps is an essential step for structure modeling, comparison of maps, and for database search. Here, we developed VESPER, which captures the similarity of underlying molecular structures embedded in density maps by taking local gradient directions into consideration. Compared to existing methods, VESPER achieved substantially more accurate global and local alignment of maps as well as database retrieval.


Asunto(s)
Microscopía por Crioelectrón/métodos , Bases de Datos Factuales , Modelos Estructurales , Programas Informáticos , Modelos Moleculares , Conformación Proteica , Proteínas/química
5.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803725

RESUMEN

The proteins with lysin motif (LysM) are carbohydrate-binding protein modules that play a critical role in the host-pathogen interactions. The plant LysM proteins mostly function as pattern recognition receptors (PRRs) that sense chitin to induce the plant's immunity. In contrast, fungal LysM blocks chitin sensing or signaling to inhibit chitin-induced host immunity. In this review, we provide historical perspectives on plant and fungal LysMs to demonstrate how these proteins are involved in the regulation of plant's immune response by microbes. Plants employ LysM proteins to recognize fungal chitins that are then degraded by plant chitinases to induce immunity. In contrast, fungal pathogens recruit LysM proteins to protect their cell wall from hydrolysis by plant chitinase to prevent activation of chitin-induced immunity. Uncovering this coevolutionary arms race in which LysM plays a pivotal role in manipulating facilitates a greater understanding of the mechanisms governing plant-fungus interactions.


Asunto(s)
Hongos/metabolismo , Inmunidad de la Planta , Proteínas/química , Proteínas/metabolismo , Secuencias de Aminoácidos , Interacciones Huésped-Patógeno , Plantas/inmunología , Plantas/microbiología
6.
Phys Rev Lett ; 126(12): 128101, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33834804

RESUMEN

Protein conformational fluctuations are highly complex and exhibit long-term correlations. Here, molecular dynamics simulations of small proteins demonstrate that these conformational fluctuations directly affect the protein's instantaneous diffusivity D_{I}. We find that the radius of gyration R_{g} of the proteins exhibits 1/f fluctuations that are synchronous with the fluctuations of D_{I}. Our analysis demonstrates the validity of the local Stokes-Einstein-type relation D_{I}∝1/(R_{g}+R_{0}), where R_{0}∼0.3 nm is assumed to be a hydration layer around the protein. From the analysis of different protein types with both strong and weak conformational fluctuations, the validity of the Stokes-Einstein-type relation appears to be a general property.


Asunto(s)
Modelos Químicos , Proteínas/química , Agua/química , Difusión , Simulación de Dinámica Molecular , Oligopéptidos/química , Conformación Proteica , Soluciones
7.
J Bioinform Comput Biol ; 19(2): 2150006, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33866960

RESUMEN

Binding site prediction for new proteins is important in structure-based drug design. The identified binding sites may be helpful in the development of treatments for new viral outbreaks in the world when there is no information available about their pockets with COVID-19 being a case in point. Identification of the pockets using computational methods, as an alternative method, has recently attracted much interest. In this study, the binding site prediction is viewed as a semantic segmentation problem. An improved 3D version of the U-Net model based on the dice loss function is utilized to predict the binding sites accurately. The performance of the proposed model on the independent test datasets and SARS-COV-2 shows the segmentation model could predict the binding sites with a more accurate shape than the recently published deep learning model, i.e. DeepSite. Therefore, the model may help predict the binding sites of proteins and could be used in drug design for novel proteins.


Asunto(s)
Biología Computacional/métodos , Proteínas/química , Proteínas/metabolismo , /química , Algoritmos , Sitios de Unión , Bases de Datos de Proteínas , Modelos Moleculares , Proteínas Virales/química , Proteínas Virales/metabolismo
8.
Molecules ; 26(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802127

RESUMEN

The aim of this work was to characterize the antioxidant properties of some of the peptides present in bromelain mung bean meal protein hydrolysate (MMPH). The MMPH was subjected to two rounds of bioassay-guided reversed-phase HPLC separation followed by peptide identification in the most potent fractions using tandem mass spectrometry. Twelve antioxidant peptides, namely, HC, CGN, LAN, CTN, LAF, CSGD, MMGW, QFAAD, ERF, EYW, FLQL, and QFAW were identified and assayed for antioxidant properties. CTN, HC, CGN, and CSGD were the most potent (p < 0.05) DPPH radical scavengers with EC50 values of 0.30, 0.29, 0.28, and 0.30 mg/mL, respectively, which are lower than the 0.03 mg/mL obtained for reduced glutathione (GSH). CTN, HC, CGN, and CSGD exhibited the most potent (p < 0.05) scavenging activities against hydroxyl and superoxide radicals with EC50 values that are similar to those of GSH. The cysteine-containing peptides also had stronger ferric reducing antioxidant power and metal chelation activity than peptides devoid of cysteine. In contrast, MMGW, ERF, and EYW had poor radical scavenging and metal chelation activities. We conclude that the availability of the sulfhydryl group may have enhanced antioxidant potency while the presence of bulky groups such phenylalanine and tryptophan had an opposite effect.


Asunto(s)
Péptidos/química , Vigna/enzimología , Vigna/metabolismo , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Quelantes , Cromatografía Líquida de Alta Presión/métodos , Depuradores de Radicales Libres/química , Glutatión/metabolismo , Radical Hidroxilo , Peroxidación de Lípido , Hidrolisados de Proteína/química , Proteínas/química , Superóxidos/química
9.
Nat Commun ; 12(1): 2200, 2021 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-33850130

RESUMEN

Split inteins are powerful tools for seamless ligation of synthetic split proteins. Yet, their use remains limited because the already intricate split site identification problem is often complicated by the requirement of extein junction sequences. To address this, we augment a mini-Mu transposon-based screening approach and devise the intein-assisted bisection mapping (IBM) method. IBM robustly reveals clusters of split sites on five proteins, converting them into AND or NAND logic gates. We further show that the use of inteins expands functional sequence space for splitting a protein. We also demonstrate the utility of our approach over rational inference of split sites from secondary structure alignment of homologous proteins, and that basal activities of highly active proteins can be mitigated by splitting them. Our work offers a generalizable and systematic route towards creating split protein-intein fusions for synthetic biology.


Asunto(s)
Inteínas/fisiología , Ingeniería de Proteínas/métodos , Proteínas/metabolismo , Escherichia coli/genética , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Inteínas/genética , Modelos Moleculares , Conformación Proteica , Empalme de Proteína , Proteínas/química , Proteínas/genética , Biología Sintética/métodos
10.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33801827

RESUMEN

Here, we summarize a line of remarkably simple, theoretical research to better understand the chemical logic by which life's standard alphabet of 20 genetically encoded amino acids evolved. The connection to the theme of this Special Issue, "Protein Structure Analysis and Prediction with Statistical Scoring Functions", emerges from the ways in which current bioinformatics currently lacks empirical science when it comes to xenoproteins composed largely or entirely of amino acids from beyond the standard genetic code. Our intent is to present new perspectives on existing data from two different frontiers in order to suggest fresh ways in which their findings complement one another. These frontiers are origins/astrobiology research into the emergence of the standard amino acid alphabet, and empirical xenoprotein synthesis.


Asunto(s)
Aminoácidos/genética , Evolución Molecular , Código Genético/genética , Biosíntesis de Proteínas , Proteínas/genética , Algoritmos , Aminoácidos/química , Biología Computacional/métodos , ADN/química , ADN/genética , Estructura Molecular , Nucleótidos/química , Nucleótidos/genética , Proteínas/química
11.
Nanomedicine (Lond) ; 16(6): 497-516, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33683164

RESUMEN

COVID-19, as an emerging infectious disease, has caused significant mortality and morbidity along with socioeconomic impact. No effective treatment or vaccine has been approved yet for this pandemic disease. Cutting-edge tools, especially nanotechnology, should be strongly considered to tackle this virus. This review aims to propose several strategies to design and fabricate effective diagnostic and therapeutic agents against COVID-19 by the aid of nanotechnology. Polymeric, inorganic self-assembling materials and peptide-based nanoparticles are promising tools for battling COVID-19 as well as its rapid diagnosis. This review summarizes all of the exciting advances nanomaterials are making toward COVID-19 prevention, diagnosis and therapy.


Asunto(s)
/diagnóstico , Nanomedicina/métodos , Nanoestructuras/uso terapéutico , Animales , /métodos , Humanos , Nanoestructuras/química , Nanotecnología/métodos , Péptidos/química , Péptidos/uso terapéutico , Polímeros/química , Polímeros/uso terapéutico , Proteínas/química , Proteínas/uso terapéutico , /aislamiento & purificación
12.
Phys Rev Lett ; 126(8): 088102, 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33709739

RESUMEN

The interaction between proteins and hydration water stabilizes protein structure and promotes functional dynamics, with water translational motions enabling protein flexibility. Engineered solvent-free protein-polymer hybrids have been shown to preserve protein structure, function, and dynamics. Here, we used neutron scattering, protein and polymer perdeuteration, and molecular dynamics simulations to explore how a polymer dynamically replaces water. Even though relaxation rates and vibrational properties are strongly modified in polymer coated compared to hydrated proteins, liquidlike polymer dynamics appear to plasticize the conjugated protein in a qualitatively similar way as do hydration-water translational motions.


Asunto(s)
Polímeros/química , Proteínas/química , Diaminas/química , Glicolatos/química , Enlace de Hidrógeno , Simulación de Dinámica Molecular , Mioglobina/química , Difracción de Neutrones , Polietilenglicoles/química , Conformación Proteica , Termodinámica , Agua/química
13.
Methods Mol Biol ; 2266: 39-72, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759120

RESUMEN

The interaction between a protein and its ligands is one of the basic and most important processes in biological chemistry. Docking methods aim to predict the molecular 3D structure of protein-ligand complexes starting from coordinates of the protein and the ligand separately. They are widely used in both industry and academia, especially in the context of drug development projects. AutoDock4 is one of the most popular docking tools and, as for any docking method, its performance is highly system dependent. Knowledge about specific protein-ligand interactions on a particular target can be used to successfully overcome this limitation. Here, we describe how to apply the AutoDock Bias protocol, a simple and elegant strategy that allows users to incorporate target-specific information through a modified scoring function that biases the ligand structure towards those poses (or conformations) that establish selected interactions. We discuss two examples using different bias sources. In the first, we show how to steer dockings towards interactions derived from crystal structures of the receptor with different ligands; in the second example, we define and apply hydrophobic biases derived from Molecular Dynamics simulations in mixed solvents. Finally, we discuss general concepts of biased docking, its performance in pose prediction, and virtual screening campaigns as well as other potential applications.


Asunto(s)
Simulación del Acoplamiento Molecular/métodos , Proteínas/química , Solventes/química , Sitios de Unión , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina/química , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Conformación Molecular , Simulación de Dinámica Molecular , Unión Proteica , Programas Informáticos , Electricidad Estática
14.
Methods Mol Biol ; 2266: 73-88, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759121

RESUMEN

The mechanism of action of covalent drugs involves the formation of a bond between their electrophilic warhead group and a nucleophilic residue of the protein target. The recent advances in covalent drug discovery have accelerated the development of computational tools for the design and characterization of covalent binders. Covalent docking algorithms can predict the binding mode of covalent ligands by modeling the bonds and interactions formed at the reaction site. Their scoring functions can estimate the relative binding affinity of ligands towards the target of interest, thus allowing virtual screening of compound libraries. However, most of the scoring schemes have no specific terms for the bond formation, and therefore it prevents the direct comparison of warheads with different intrinsic reactivity. Herein, we describe a protocol for the binding mode prediction of covalent ligands, a typical virtual screening of compound sets with a single warhead chemistry, and an alternative approach to screen libraries that include various warhead types, as applied in recently validated studies.


Asunto(s)
Química Computacional/métodos , Descubrimiento de Drogas/métodos , Simulación del Acoplamiento Molecular/métodos , Proteínas/química , Algoritmos , Sitios de Unión , Bases de Datos de Proteínas , Ligandos , Modelos Moleculares , Conformación Molecular , Unión Proteica , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/química , Programas Informáticos , Relación Estructura-Actividad
15.
Methods Mol Biol ; 2266: 89-104, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759122

RESUMEN

In silico rational drug design is one of the major pylons in the drug discovery process. Drugs usually act on specific targets such as proteins, DNA, and lipid bilayers. Thus, molecular docking is an essential part of the rational drug design process. Molecular docking uses specific algorithms and scoring functions to reveal the strength of the interaction of the ligand to its target. AutoDock is a molecular docking suite that offers a variety of algorithms to tackle specific problems. These algorithms include Monte Carlo Simulated Annealing (SA), a Genetic Algorithm (GA), and a hybrid local search GA, also known as the Lamarckian Genetic Algorithm (LGA). This chapter aims to acquaint the reader with the docking process using AutoDockTools (GUI of AutoDock). Furthermore, herein is described the docking process of calf thymus DNA with three metal complexes, as a potential metallo-therapeutics as also the docking process of the plant flavonoid quercetin to the antiapoptotic protein BcL-xL.


Asunto(s)
ADN/química , Descubrimiento de Drogas/métodos , Metales/química , Simulación del Acoplamiento Molecular/métodos , Proteínas/química , Algoritmos , Simulación por Computador , Diseño de Fármacos , Ligandos , Unión Proteica , Quercetina/química , Programas Informáticos , Proteína bcl-X/química
16.
Methods Mol Biol ; 2266: 105-124, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759123

RESUMEN

Interactions between enzymes and small molecules lie in the center of many fundamental biochemical processes. Their analysis using molecular dynamics simulations have high computational demands, geometric approaches fail to consider chemical forces, and molecular docking offers only static information. Recently, we proposed to combine molecular docking and geometric approaches in an application called CaverDock. CaverDock is discretizing enzyme tunnel into discs, iteratively docking with restraints into one disc after another and searching for a trajectory of the ligand passing through the tunnel. Here, we focus on the practical side of its usage describing the whole method: from getting the application, and processing the data through a workflow, to interpreting the results. Moreover, we shared the best practices, recommended how to solve the most common issues, and demonstrated its application on three use cases.


Asunto(s)
Descubrimiento de Drogas/métodos , Simulación del Acoplamiento Molecular/métodos , Proteínas/química , Ácido Araquidónico/química , Sitios de Unión , Clorhidrinas/química , Sistema Enzimático del Citocromo P-450/química , Diseño de Fármacos , Etanol/análogos & derivados , Etanol/química , Dibromuro de Etileno/química , Hidrolasas/química , Ligandos , Simulación de Dinámica Molecular , Unión Proteica , Programas Informáticos , Relación Estructura-Actividad , Termodinámica
17.
Methods Mol Biol ; 2266: 125-140, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759124

RESUMEN

Rational drug discovery relies heavily on molecular docking-based virtual screening, which samples flexibly the ligand binding poses against the target protein's structure. The upside of flexible docking is that the geometries of the generated docking poses are adjusted to match the residue alignment inside the target protein's ligand-binding pocket. The downside is that the flexible docking requires plenty of computing resources and, regardless, acquiring a decent level of enrichment typically demands further rescoring or post-processing. Negative image-based screening is a rigid docking technique that is ultrafast and computationally light but also effective as proven by vast benchmarking and screening experiments. In the NIB screening, the target protein cavity's shape/electrostatics is aligned and compared against ab initio-generated ligand 3D conformers. In this chapter, the NIB methodology is explained at the practical level and both its weaknesses and strengths are discussed candidly.


Asunto(s)
Descubrimiento de Drogas/métodos , Simulación del Acoplamiento Molecular/métodos , Proteínas/química , Algoritmos , Sitios de Unión , Cristalografía por Rayos X , Ciclooxigenasa 2/química , Bases de Datos de Proteínas , Ligandos , Modelos Moleculares , Conformación Molecular , Unión Proteica , Curva ROC , Bibliotecas de Moléculas Pequeñas/química , Programas Informáticos , Electricidad Estática , Interfaz Usuario-Computador
18.
Methods Mol Biol ; 2266: 141-154, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759125

RESUMEN

Molecular docking produces often lackluster results in real-life virtual screening assays that aim to discover novel drug candidates or hit compounds. The problem lies in the inability of the default docking scoring to properly estimate the Gibbs free energy of binding, which impairs the recognition of the best binding poses and the separation of active ligands from inactive compounds. Negative image-based rescoring (R-NiB) provides both effective and efficient way for re-ranking the outputted flexible docking poses to improve the virtual screening yield. Importantly, R-NiB has been shown to work with multiple genuine drug targets and six popular docking algorithms using demanding benchmark test sets. The effectiveness of the R-NiB methodology relies on the shape/electrostatics similarity between the target protein's ligand-binding cavity and the docked ligand poses. In this chapter, the R-NiB method is described with practical usability in mind.


Asunto(s)
Descubrimiento de Drogas/métodos , Simulación del Acoplamiento Molecular/métodos , Proteínas/química , Algoritmos , Área Bajo la Curva , Sitios de Unión , Cristalografía por Rayos X , Ciclooxigenasa 2/química , Bases de Datos de Proteínas , Ligandos , Conformación Molecular , Neuraminidasa/química , Unión Proteica , Programas Informáticos , Electricidad Estática
19.
Methods Mol Biol ; 2266: 171-186, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759127

RESUMEN

Comparative Binding Energy (COMBINE) analysis is an approach for deriving a target-specific scoring function to compute binding free energy, drug-binding kinetics, or a related property by exploiting the information contained in the three-dimensional structures of receptor-ligand complexes. Here, we describe the process of setting up and running COMBINE analysis to derive a Quantitative Structure-Kinetics Relationship (QSKR) for the dissociation rate constants (koff) of inhibitors of a drug target. The derived QSKR model can be used to estimate residence times (τ, τ=1/koff) for similar inhibitors binding to the same target, and it can also help to identify key receptor-ligand interactions that distinguish inhibitors with short and long residence times. Herein, we demonstrate the protocol for the application of COMBINE analysis on a dataset of 70 inhibitors of heat shock protein 90 (HSP90) belonging to 11 different chemical classes. The procedure is generally applicable to any drug target with known structural information on its complexes with inhibitors.


Asunto(s)
Descubrimiento de Drogas/métodos , Proteínas HSP90 de Choque Térmico/química , Preparaciones Farmacéuticas/química , Programas Informáticos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Cinética , Ligandos , Unión Proteica , Proteínas/antagonistas & inhibidores , Proteínas/química , Relación Estructura-Actividad Cuantitativa , Termodinámica
20.
Methods Mol Biol ; 2266: 187-202, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33759128

RESUMEN

Multicanonical molecular dynamics (McMD)-based dynamic docking has been applied to predict the native binding configurations for several protein receptors and their ligands. Due to the enhanced sampling capabilities of McMD, it can exhaustively sample bound and unbound ligand configurations, as well as receptor conformations, and thus enables efficient sampling of the conformational and configurational space, not possible using canonical MD simulations. As McMD samples a wide configurational space, extensive analysis is required to study the diverse ensemble consisting of bound and unbound structures. By projecting the reweighted ensemble onto the first two principal axes obtained via principal component analysis of the multicanonical ensemble, the free energy landscape (FEL) can be obtained. Further analysis produces representative structures positioned at the local minima of the FEL, where these structures are then ranked by their free energy. In this chapter, we describe our dynamic docking methodology, which has successfully reproduced the native binding configuration for small compounds, medium-sized compounds, and peptide molecules.


Asunto(s)
Anticuerpos/química , Simulación del Acoplamiento Molecular/métodos , Simulación de Dinámica Molecular , Péptidos/química , Proteínas/química , Secretasas de la Proteína Precursora del Amiloide/química , Anticuerpos Monoclonales Humanizados/química , Ácido Aspártico Endopeptidasas/química , Quinasa 2 Dependiente de la Ciclina/química , Bases de Datos de Proteínas , Ligandos , Modelos Moleculares , Conformación Molecular , Análisis de Componente Principal , Unión Proteica , Temperatura
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