RESUMEN
Amphiphobic fluoroalkyl chains are exploited for creating robust and diverse self-assembled biomimetic catalysts. Long terminal perfluoroalkyl chains (Cn F2n+1 with n=6, 8, and 10) linked with a short perhydroalkyl chains (Cm H2m with m=2 and 3) were used to synthesize several 1,4,7-triazacyclononane (TACN) derivatives, Cn F2n+1 -Cm H2m -TACN. In the presence of an equimolar amount of Zn2+ ions that coordinate the TACN moiety and drive the self-assembly into micelle-like aggregates, the critical aggregation concentration of polyfluorinated Cn F2n+1 -Cm H2m -TACNâ Zn2+ was lowered by â¼1 order of magnitude compared to the traditional perhyroalkyl counterpart with identical carbon number of alkyl chain. When 2'-hydroxypropyl-4-nitrophenyl phosphate was used as the model phosphate substrate, polyfluorinated Cn F2n+1 -Cm H2m -TACNâ Zn2+ assemblies showed higher affinity and catalytic activity, compared to its perhyroalkyl chain-based counterpart. Coarse-grained molecular dynamic simulations have been introduced to explore the supramolecular assembly of polyfluoroalkyl chains in the presence of Zn2+ ions and to better understand their enhanced catalytic activity.
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Novel fluorinated foldamers based on aminomethyl-1,4-triazolyl-difluoroacetic acid (1,4-Tz-CF2) units were synthesized and their conformational behaviour was studied by NMR and molecular dynamics. Their activity on the aggregation of the human islet amyloid polypeptide (hIAPP) amyloid protein was evaluated by fluorescence spectroscopy and mass spectrometry. The fluorine labelling of these foldamers allowed the analysis of their interaction with the target protein. We demonstrated that the preferred extended conformation of homotriazolamers of 1,4-Tz-CF2 unit increases the aggregation of hIAPP, while the hairpin-like conformation of more flexible heterotriazolamers containing two 1,4-Tz-CF2 units mixed with natural amino acids from the hIAPP sequence reduces it, and more efficiently than the parent natural peptide. The longer heterotriazolamers having three 1,4-Tz-CF2 units adopting more folded hairpin-like and ladder-like structures similar to short multi-stranded ß-sheets have no effect. This work demonstrates that a good balance between the structuring and flexibility of these foldamers is necessary to allow efficient interaction with the target protein.
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Polipéptido Amiloide de los Islotes Pancreáticos , Triazoles , Polipéptido Amiloide de los Islotes Pancreáticos/química , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Humanos , Triazoles/química , Simulación de Dinámica Molecular , Halogenación , Agregado de ProteínasRESUMEN
To achieve drug release from polymer prodrug nanoparticles, the drug-polymer linker must be accessible for cleavage to release the drug, which can occur under certain physiological conditions (e.g., presence of specific enzymes). Supramolecular organization of polymer prodrug nanoparticles is crucial as it greatly affects the location of the linker, its surface exposure/solvation and thus its cleavage to release the drug. Since experimental access to these data is not straightforward, new methodologies are critically needed to access this information and to accelerate the development of more effective polymer prodrug nanoparticles, and replace the time-consuming and resource-intensive traditional trial-and-error strategy. In this context, we reported here the use of a coarse-grained model to assist the design of polymer prodrug nanoparticles with enhanced cytotoxicity. By choosing the solvent accessible surface area as the critical parameter for predicting drug release and hence cytotoxicity of polymer prodrug nanoparticles, we developed an optimized polymer-drug linker with enhanced hydrophilicity and solvation. Our hypothesis was then experimentally validated by the synthesis of the corresponding polymer prodrugs based on two different drugs (gemcitabine and paclitaxel), which demonstrated greater performances in terms of drug release and cytotoxicity on two cancer cell lines. Interestingly, our methodology can be easily applied to other polymer prodrug structures, which would contribute to the development of more efficient drug delivery systems via in silico screening.
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Nanopartículas , Profármacos , Profármacos/farmacología , Profármacos/química , Polímeros , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Gemcitabina , Liberación de Fármacos , Línea Celular TumoralRESUMEN
Over the past decades, many cell-penetrating peptides (CPP) have been studied for their capacity to cross cellular membranes, mostly in order to improve cellular uptake of therapeutic agents. Even though hydrophobic and anionic CPPs have been described, many of them are polycationic, due to the presence of several arginine (Arg) residues. Noteworthy, however, the presence of aromatic amino acids such as tryptophan (Trp) within CPPs seems to play an important role to reach high membranotropic activity. RW9 (RRWWRRWRR) is a designed CPP derived from the polyarginine R9 presenting both features. In general, when interacting with membranes, CPPs adopt an optimal conformation for membrane interactions - an amphipathic helical secondary structure in the case of RW9. Herein, we assumed that the incorporation of a locally constrained amino acid in the peptide sequence could improve the membranotropic activity of RW9, by facilitating its structuration upon contact with a membrane, while leaving a certain plasticity. Therefore, two cyclized Trp derivatives (Tcc and Aia) were synthesized to be incorporated in RW9 as surrogates of Trp residues. Thus, a series of peptides containing these building blocks has been synthesized by varying the type, position, and number of modifications. The membranotropic activity of the RW9 analogs was studied by spectrofluorescence titration of the peptides in presence of liposomes (DMPG), allowing to calculate partition coefficients (Kp). Our results indicate that the partitioning of the modified peptides depends on the type, the number and the position of the modification, with the best sequence being [Aia4]RW9. Interestingly, both NMR analysis and molecular dynamic (MD) simulations indicate that this analog presents an extended conformation similar to the native RW9, but with a much-reduced structural flexibility. Finally, cell internalization properties were also confirmed by confocal microscopy.
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Péptidos de Penetración Celular , Péptidos de Penetración Celular/farmacología , Péptidos de Penetración Celular/química , Membrana Celular/metabolismo , Secuencia de Aminoácidos , Liposomas/química , Simulación de Dinámica MolecularRESUMEN
The early characterization of drug membrane permeability is an important step in pharmaceutical developments to limit possible late failures in preclinical studies. This is particularly crucial for therapeutic peptides whose size generally prevents them from passively entering cells. However, a sequence-structure-dynamics-permeability relationship for peptides still needs further insight to help efficient therapeutic peptide design. In this perspective, we conducted here a computational study for estimating the permeability coefficient of a benchmark peptide by considering and comparing two different physical models: on the one hand, the inhomogeneous solubility-diffusion model, which requires umbrella-sampling simulations, and on the other hand, a chemical kinetics model which necessitates multiple unconstrained simulations. Notably, we assessed the accuracy of the two approaches in relation to their computational cost.
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Membrana Dobles de Lípidos , Simulación de Dinámica Molecular , Membrana Dobles de Lípidos/química , Permeabilidad de la Membrana Celular , Difusión , Péptidos , PermeabilidadRESUMEN
Protein-protein interactions (PPIs) play crucial roles in many cellular processes and their deregulation often leads to cellular dysfunctions. One promising way to modulate PPIs is to use peptide derivatives that bind their protein target with high affinity and high specificity. Peptide modulators are often designed using secondary structure mimics. However, fragment-based design is an alternative emergent approach in the PPI field. Most of the reported computational fragment-based libraries targeting PPIs are composed of small molecules or already approved drugs, but, according to our knowledge, no amino acid based library has been reported yet. In this context, we developed a novel fragment-based approach called Des3PI (design of peptides targeting protein-protein interactions) with a library composed of natural amino acids. All the amino acids are docked into the target surface using Autodock Vina. The resulting binding modes are geometrically clustered, and, in each cluster, the most recurrent amino acids are identified and form the hotspots that will compose the designed peptide. This approach was applied on Ras and Mcl-1 proteins, as well as on A[Formula: see text] protofibril. For each target, at least five peptides generated by Des3PI were tested in silico: the peptides were first blindly docked on their target, and then, the stability of the successfully docked complexes was verified using 200 ns MD simulations. Des3PI shows very encouraging results by yielding at least 3 peptides for each protein target that succeeded in passing the two-step assessment.
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Péptidos Cíclicos , Proteínas , Simulación del Acoplamiento Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Péptidos/química , Unión Proteica , Estructura Secundaria de Proteína , Proteínas/químicaRESUMEN
Drug-polymer conjugates that can self-assemble into nanoparticles are promising drug delivery systems that improve the drug bioavailability and allow their controlled release. However, despite the possibility of reaching high drug loadings, the efficiency of the drug release, mediated by cleavage of the drug-polymer linker, is a key parameter to obtain significant anticancer activity. To overcome the limitations of experimental characterizations and to gain a better understanding of such systems, we conducted a coarse-grained molecular dynamics simulation study on four representative drug-polymer conjugates obtained by the "drug-initiated" method and studied their supramolecular organization upon self-assembly. The prodrugs were composed of either a gemcitabine or a paclitaxel anticancer drug, either a propanoate or a diglycolate linker, and a polyisoprene chain. Our simulations gave crucial information concerning the spatial organization of the different components (e.g., drug, linker, polymer, etc.) into the nanoparticles and revealed that the linkers are not fully accessible to the solvent. Notably, some cleavage sites were either poorly hydrated or partially solvated. These observations might account for the low efficiency of drug release from the nanoparticles, particularly when the linker is too short and/or not hydrophilic/solvated enough. We believe that our theoretical study could be adapted to other types of polymer prodrugs and could guide the design of new polymer prodrug nanoparticles with improved drug release efficiency.
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Desoxicitidina/análogos & derivados , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/análogos & derivados , Polímeros/química , Profármacos/química , Desoxicitidina/química , Liberación de Fármacos , Interacciones Hidrofóbicas e Hidrofílicas , Simulación de Dinámica Molecular , GemcitabinaRESUMEN
DciA is a newly discovered bacterial protein involved in loading the replicative helicase DnaB onto DNA at the initiation step of chromosome replication. Its three-dimensional structure is composed of a folded N-terminal domain (residues 1-111) resembling K Homology domains and a long disordered C-terminal tail (residues 112-157) which structure-activity relationship remains to be elucidated. In the present study on Vibrio cholerae DciA, we emphasize the importance of its disordered region to load DnaB onto DNA using surface plasmon resonance (SPR) and isothermal titration microcalorimetry (ITC). Then we characterize the conformational ensemble of the full-length protein using a combination of circular dichroism (CD), small angle X-ray scattering (SAXS), and molecular dynamics (MD) simulations. The atomic-level structural ensemble generated by MD simulations is in very good agreement with SAXS data. From initial conformations of the C-terminal tail without any secondary structure, our simulations bring to light several transient helical structures in this segment, which might be molecular recognition features (MoRFs) for the binding to DnaB and its recruitment and loading onto DNA.
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Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , ADN/metabolismo , AdnB Helicasas/química , AdnB Helicasas/metabolismo , Simulación de Dinámica Molecular , Estructura Secundaria de Proteína , Dispersión del Ángulo Pequeño , Relación Estructura-Actividad , Vibrio cholerae/metabolismo , Difracción de Rayos X/métodosRESUMEN
Because of their large conformational heterogeneity, structural characterization of intrinsically disordered proteins (IDPs) is very challenging using classical experimental methods alone. In this study, we use NMR and small-angle x-ray scattering (SAXS) data with multiple molecular dynamics (MD) simulations to describe the conformational ensemble of the fully disordered verprolin homology domain of the neural Aldrich syndrome protein involved in the regulation of actin polymerization. First, we studied several back-calculation software of SAXS scattering intensity and optimized the adjustable parameters to accurately calculate the SAXS intensity from an atomic structure. We also identified the most appropriate force fields for MD simulations of this IDP. Then, we analyzed four conformational ensembles of neural Aldrich syndrome protein verprolin homology domain, two generated with the program flexible-meccano with or without NMR-derived information as input and two others generated by MD simulations with two different force fields. These four conformational ensembles were compared to available NMR and SAXS data for validation. We found that MD simulations with the AMBER-03w force field and the TIP4P/2005s water model are able to correctly describe the conformational ensemble of this 67-residue IDP at both local and global level.
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Proteínas Intrínsecamente Desordenadas/química , Proteína del Síndrome de Wiskott-Aldrich/química , Humanos , Espectroscopía de Resonancia Magnética , Simulación de Dinámica Molecular , Dominios Proteicos , Dispersión del Ángulo Pequeño , Difracción de Rayos XRESUMEN
The concept of intrinsically disordered proteins (IDPs) has emerged relatively slowly, but over the past 20 years, it has become an intense research area in structural biology. Indeed, because of their considerable flexibility and structural heterogeneity, the determination of IDP conformational ensemble is particularly challenging and often requires a combination of experimental measurements and computational approaches. With the improved accuracy of all-atom force fields and the increasing computing performances, molecular dynamics (MD) simulations have become more and more reliable to generate realistic conformational ensembles. And the combination of MD simulations with experimental approaches, such as nuclear magnetic resonance (NMR) and/or small-angle X-ray scattering (SAXS) allows one to converge toward a more accurate and exhaustive description of IDP structures. In this Review, we discuss the state of the art of MD simulations of IDP conformational ensembles, with a special focus on studies that back-calculated and directly compared theoretical and experimental NMR or SAXS observables, such as chemical shifts (CS), 3J-couplings (3Jc), residual dipolar couplings (RDC), or SAXS intensities. We organize the review in three parts. In the first section, we discuss the studies which used NMR and/or SAXS data to test and validate the development of force fields or enhanced sampling techniques. In the second part, we explore different methods for the refinement of MD-derived structural ensembles, such as NMR or SAXS data-restrained MD simulations or ensemble reweighting to better fit experiments. Finally, we survey some recent studies combining MD simulations with NMR and/or SAXS measurements to investigate the relationship between IDP conformational ensemble and biological activity, as well as their implication in human diseases. From this review, we noticed that quite a few studies compared MD-generated conformational ensembles with both NMR and SAXS measurements to validate IDP structures at both local and global levels. Yet, beside the IDP propensity to form local secondary structures, their dynamic extension or compactness also appears important for their activity. Thus, we believe that a close synergy between MD simulations, NMR, and SAXS experiments would be greatly appropriate to address the challenges of characterizing the disordered structures of proteins and their complexes, relative to their biological functions.
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Proteínas Intrínsecamente Desordenadas/química , Simulación de Dinámica Molecular , Péptidos/química , Proteínas Amiloidogénicas/química , Animales , Humanos , Resonancia Magnética Nuclear Biomolecular , Conformación Proteica , Dispersión del Ángulo Pequeño , Proteínas Virales/química , Difracción de Rayos XRESUMEN
Cellular regulation or signaling processes are mediated by many proteins which often have one or several intrinsically disordered regions (IDRs). These IDRs generally serve as binders to different proteins with high specificity. In many cases, IDRs undergo a disorder-to-order transition upon binding, following a mechanism between two possible pathways, the induced fit or the conformational selection. Since these mechanisms contribute differently to the kinetics of IDR associations, it is important to investigate them in order to gain insight into the physical factors that determine the biomolecular recognition process. The verprolin homology domain (V) of the Neural Wiskott-Aldrich Syndrome Protein (N-WASP), involved in the regulation of actin polymerization, is a typical example of IDR. It is composed of two WH2 motifs, each being able to bind one actin molecule. In this study, we investigated the early steps of the recognition process of actin by the WH2 motifs of N-WASP domain V. Using docking calculations and molecular dynamics simulations, our study shows that actin is first recognized by the N-WASP domain V regions which have the highest propensity to form transient α -helices. The WH2 motif consensus sequences "LKKV" subsequently bind to actin through large conformational changes of the disordered domain V.
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Actinas/metabolismo , Proteína del Síndrome de Wiskott-Aldrich/química , Proteína del Síndrome de Wiskott-Aldrich/metabolismo , Actinas/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Probabilidad , Dominios Proteicos , Multimerización de Proteína , Factores de TiempoRESUMEN
Pentapeptides having the sequence R-HN-Ala-Val-X-Val-Leu-OMe, where the central residue X is L-serine, L-threonine, (2S,3R)-L-CF3-threonine and (2S,3S)-L-CF3-threonine were prepared. The capacity of (2S,3S)- and (2S,3R)-CF3-threonine analogues to stabilize an extended structure when introduced in the central position of pentapeptides is demonstrated by NMR conformational studies and molecular dynamics simulations. CF3-threonine containing pentapeptides are more prone to mimic ß-strands than their natural Ser and Thr pentapeptide analogues. The proof of concept that these fluorinated ß-strand mimics are able to disrupt protein-protein interactions involving ß-sheet structures is provided. The CF3-threonine containing pentapeptides interact with the amyloid peptide Aß1-42 in order to reduce the protein-protein interactions mediating its aggregation process.
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The human islet amyloid polypeptide (hIAPP) is an intrinsically disordered protein that can self-assemble into fibrillar aggregates that play a key role in the pathogenesis of the type II diabetes mellitus. hIAPP can transiently adopt α -helix and ß -strand conformations that could be important intermediate species on the fibrillization pathway. However, experimental studies of the monomeric peptide conformations are limited due to its high aggregation propensity, and the early steps of the hIAPP association are not clearly characterized. In particular, the question of whether the aggregation-prone conformation is α -helical or ß -strand-rich is still debated. In this study, combining extensive all-atom molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations in explicit water, we shed some light on the differences between the amidated and non-amidated hIAPP conformational ensembles. Our study shows that, when compared to the amidated monomer, the non-amidation of hIAPP induces a significantly lower propensity to form ß -strands, especially aggregation-prone ß -hairpins. Since the fibrillization of the non-amidated hIAPP is significantly slower than that of the amidated peptide, this indicates that the early steps of the peptide oligomerization involve the association of ß -hairpins or ß -strands structures.
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Amiloide/química , Polipéptido Amiloide de los Islotes Pancreáticos/química , Amidas/química , Humanos , Cinética , Simulación de Dinámica Molecular , Agregación Patológica de Proteínas , Pliegue de Proteína , Procesamiento Proteico-Postraduccional , Estructura Cuaternaria de Proteína , Estructura Secundaria de Proteína , TermodinámicaRESUMEN
Coarse-grained models are more and more frequently used in the studies of the proteins structural and dynamic properties, since the reduced number of degrees of freedom allows to enhance the conformational space exploration. This chapter attempts to provide an overview of the various coarse-grained models that were applied to study the functional conformational changes of the polypeptides main chain around their native state. It will more specifically discuss the methods used to represent the protein backbone flexibility and to account for the physico-chemical interactions that stabilize the secondary structure elements.
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Simulación de Dinámica Molecular , Proteínas/química , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Pliegue de Proteína , Estabilidad Proteica , Estructura Secundaria de Proteína , TermodinámicaRESUMEN
Many protein-protein interactions result from the binding of one folded protein with one short peptide segment, such as complexes formed by SH3 or PDZ domains. These transient protein-peptide interactions are notably involved in cellular signaling pathways and generally have low affinities, which opens the possibility to design competitive inhibitors of these complexes. We present and assess here our computational approach, called Des3PI, to design de novo cyclic peptides with potential high affinity for protein surfaces involved in interactions with peptide segments. The results were not conclusive for two receptors, the αVß3 integrin and the CXCR4 chemokine receptor, but were promising in the case of SH3 and PDZ domains: For the former, Des3PI was able to find at least one cyclic sequence with six hotspots that binds a SH3 domain with a better theoretical affinity to the known proline-rich RLP2 peptide. For the latter, Des3PI could identify at least four cyclic sequences with four or five hotspots that have lower binding free energies computed by the MM-PBSA method than the reference peptide GKAP.
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Péptidos Cíclicos , Péptidos , Secuencia de Aminoácidos , Péptidos Cíclicos/metabolismo , Unión Proteica , Péptidos/química , Proteínas de la Membrana/metabolismo , Dominios Homologos src , Sitios de UniónRESUMEN
A novel class of peptidomimetic foldamers based on diaza-peptide units are reported. Circular dichroism, attenuated total reflection -Fourier transform infrared, NMR, and molecular dynamics studies demonstrate that unlike the natural parent nonapeptide, the specific incorporation of one diaza-peptide unit at the N-terminus allows helical folding in water, which is further reinforced by the introduction of a second unit at the C-terminus. The ability of these foldamers to resist proteolysis, to mimic the small helical hot spot of transthyretin-amyloid ß (Aß) cross-interaction, and to decrease pathological Aß aggregation demonstrates that the introduction of diaza-peptide units is a valid approach for designing mimics or inhibitors of protein-protein interaction and other therapeutic peptidomimetics. This study also reveals that small peptide foldamers can play the same role as physiological chaperone proteins and opens a new way to design inhibitors of amyloid protein aggregation, a hallmark of more than 20 serious human diseases such as Alzheimer's disease.
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Enfermedad de Alzheimer , Dermatitis , Peptidomiméticos , Humanos , Péptidos beta-Amiloides , Chaperonas Moleculares , Proteínas Amiloidogénicas , Dicroismo Circular , Peptidomiméticos/farmacologíaRESUMEN
Connexins are structurally related transmembrane proteins that assemble to form gap junction channels involved in the mediation of intercellular communication. It has been shown that the intracellular tail of connexin43 (Cx43) interacts with tubulin and microtubules with putative impacts on its own intracellular trafficking, its activity in channel communication, and its interference with specific growth factor signal transduction cascades. We demonstrate here that the microtubule binding of Cx43 is mainly driven by a short region of 26 amino acid residues located within the intracellular tail of Cx43. The nuclear magnetic resonance structural analysis of a peptide (K26D) corresponding to this region shows that this peptide is unstructured when free in solution and adopts a helix conformation upon binding with tubulin. In addition, the resulting K26D-tubulin molecular complex defines a new structural organization that could be shared by other microtubule partners. Interestingly, the K26D-tubulin interaction is prevented by the phosphorylation of K26D at a src kinase specific site. Altogether, the results elucidate the mechanism of the interaction of Cx43 with the microtubule cytoskeleton and propose a pathway for understanding the microtubule-dependent regulation of Cx43 gap junctional communications and the involvement of Cx43 in TGF-ß signal transduction.
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Conexina 43/química , Conexina 43/metabolismo , Microtúbulos/metabolismo , Tubulina (Proteína)/metabolismo , Secuencia de Aminoácidos , Animales , Comunicación Celular , Conexina 43/genética , Cristalografía por Rayos X , Uniones Comunicantes/metabolismo , Humanos , Técnicas In Vitro , Modelos Moleculares , Datos de Secuencia Molecular , Resonancia Magnética Nuclear Biomolecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Fosforilación , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , OvinosRESUMEN
Protein-protein interactions play crucial and subtle roles in many biological processes and modifications of their fine mechanisms generally result in severe diseases. Peptide derivatives are very promising therapeutic agents for modulating protein-protein associations with sizes and specificities between those of small compounds and antibodies. For the same reasons, rational design of peptide-based inhibitors naturally borrows and combines computational methods from both protein-ligand and protein-protein research fields. In this chapter, we aim to provide an overview of computational tools and approaches used for identifying and optimizing peptides that target protein-protein interfaces with high affinity and specificity. We hope that this review will help to implement appropriate in silico strategies for peptide-based drug design that builds on available information for the systems of interest.
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Péptidos , Proteínas , Fenómenos Biofísicos , Ligandos , Péptidos/química , Péptidos/farmacología , Proteínas/químicaRESUMEN
Poly(ornithine-co-citrulline)s are ureido-based polymers, which were shown to exhibit tunable upper critical solution temperature (UCST) behavior, a property that can be exploited to develop thermoresponsive nanoparticles for controlled drug delivery systems. To gain insight into the driving forces that govern the formation and dissolution processes of poly(ornithine-co-citrulline) nanoparticles, a molecular dynamics (MD) simulation study has been carried out using MARTINI-based protein coarse-grained models. Multi-microsecond simulations at temperatures ranging from 280 to 370 K show that the fully reparametrized version 3.0 of MARTINI force field is able to capture the dependence on temperature of poly(ornithine-co-citrulline) aggregation and dissolution, while version 2.2 could not account for it. Furthermore, the phase separation observed in these simulations allowed us to extrapolate a phase diagram based on the Flory-Huggins theory of polymer solution, which could help in future rational design of drug delivery nanoparticles based on poly(amino acid)s.
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The Ministère de l'Enseignement Supérieur et de la Recherche (MESR) is thanked for financial support for José Laxio Arenas. The China Scholarship Council is thanked for financial support for Yaochun Xu. The authors thank Pr. Vadim Soloshonok and TOSOH F-TECH, Inc. for the kind gift of N-terbutyl-sulfinylimine.