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1.
Nature ; 579(7797): 152-157, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32076264

RESUMO

GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders1,2. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric Gs protein2, but it is unclear how GPR52 and Gs couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a Gs-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR523. A fully active state is achieved when Gs is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.


Assuntos
Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Regulação Alostérica , Sítio Alostérico , Motivos de Aminoácidos , Sequência de Aminoácidos , Apoproteínas/agonistas , Apoproteínas/química , Apoproteínas/metabolismo , Sítios de Ligação , Microscopia Crioeletrônica , Cristalografia por Raios X , Subunidades alfa Gs de Proteínas de Ligação ao GTP/química , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/ultraestrutura , Humanos , Ligantes , Modelos Moleculares , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/ultraestrutura
2.
Chem Commun (Camb) ; 56(8): 1271-1274, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31903456

RESUMO

A dual-cavity basket 16-, holding six γ-aminobutyric acids at its termini, encapsulates variously sized aromatics 2-7+, including four anthracyclines (8+-11+), driven by the hydrophobic effect and hydrogen bonding (HB). In particular, the formation of stable (K = 1012 M-2) anthracycline complexes [(8+-11+)2⊂16-], assembled into nanoparticles, occurred with positive homotropic cooperativity (α = 4K2/K1 = 1.1 ± 0.3 × 102-1.3 ± 0.7 × 103) in PBS medium. Importantly, weakening the first binding event (K1, i.e. by removing HBs) turned the second one (K2) more favorable. The finding is of interest for developing cooperative nano-antidotes acting as biodetoxifying agents.


Assuntos
Antraciclinas/farmacologia , Antídotos/farmacologia , Antineoplásicos/farmacologia , Nanoestruturas/química , Regulação Alostérica/efeitos dos fármacos , Antraciclinas/síntese química , Antraciclinas/química , Antídotos/síntese química , Antídotos/química , Antineoplásicos/química , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estrutura Molecular
3.
J Phys Chem Lett ; 11(3): 864-868, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31940206

RESUMO

The transcriptional adaptor zinc-binding 1 (TAZ1) domain of the transcriptional coactivator CBP/P300 and two disordered peptides, HIF-1α and CITED2, form a delicate protein switch that regulates cellular hypoxic response. In hypoxia, HIF-1α binds TAZ1 to control the transcription of adaptive genes critical for the recovery from hypoxic stress. CITED2 acts as the negative feedback regulator to rapidly displace HIF-1α and efficiently attenuate the hypoxic response. Though CITED2 and HIF-1α have the same dissociation constant (Kd = 10 nM) in their binary complexes with TAZ1, CITED2 is much more competitive than HIF-1α upon binding the same target TAZ1 in ternary ( Berlow et al. Nature 2017 , 543 , 447 - 451 ). Here we demonstrate that a simple coarse-grained model can recapitulate this negative allosteric effect and provide detailed physical insights into the displacement mechanism. We find that long-range electrostatic forces are essential for the efficient displacement of HIF-1α by CITED2. The strong electrostatic interactions between CITED2 and TAZ1, along with the unique binding mode, make CITED2 much more competitive than HIF-1α in binding TAZ1.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Proteínas Repressoras/química , Transativadores/química , Fatores de Transcrição de p300-CBP/química , Regulação Alostérica , Humanos , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , Eletricidade Estática
4.
Eur J Med Chem ; 186: 111881, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31780081

RESUMO

A scaffold hopping strategy converted the known 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidine core (1 and 2) by cyclization to a fused [6 + 5+6] membered heterocyclic mGluR2 PAM scaffold. Pharmacophore guided structure-activity relationship (SAR) studies resulted in a series of potent and metabolically stable mGluR2 PAMs. A representative optimized compound (95) having the most balanced profile, demonstrated efficacy in the PCP-induced hyper-locomotion model in mice that revealed the new chemotype being a promising PAM lead targeting mGluR2 receptors and providing support for further translational studies.


Assuntos
Benzimidazóis/farmacologia , Descoberta de Drogas , Pirazinas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Benzimidazóis/química , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirazinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
5.
Comput Biol Chem ; 84: 107194, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31881526

RESUMO

The tumor suppressor p53, a transcription factor, plays a critical role in many cellular processes, including DNA repair and apoptosis and cell cycle arrest. Missense mutations in the p53 have closely related to human cancer. R249S mutation at the p53 core DNA binding domain (DBD) is frequently observed in hepatocellular carcinoma. This mutation is away from the p53 DBD-DNA binding interface. However, how the R249S mutation causes the structural changes of p53 DBD that lead to weak the binding of p53 mutant to DNA has not been clearly understood. Here, microsecond-scale molecular dynamics (MD) simulations of p53 DBD in the wild type (WT) and R249S mutated states in the absence of DNA binding were performed to explore the effect of the R249S mutation on the conformational dynamics of p53 DBD. The R249S mutation does not cause the global conformational changes, and it only affects the local domains at the mutation site and the DNA binding interface, particularly at the S1-S2 turn. The allosteric effects of the S1-S2 turn induced by the R249S mutation lead to the extension of the S1-S2 turn into the ß-strands, which in turn interferes with the binding of DNA at the major groove. The results can help decipher the allosteric regulatory mechanism by which the R249S mutation of p53 DBD affects the p53 DBD-DNA interactions.


Assuntos
Neoplasias Hepáticas/genética , Simulação de Dinâmica Molecular , Proteína Supressora de Tumor p53/genética , Regulação Alostérica , Sítios de Ligação , Humanos , Mutação , Proteína Supressora de Tumor p53/metabolismo
6.
J Chem Phys ; 151(21): 215101, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31822099

RESUMO

The fact that allostery, a nonlocal signaling between distant binding sites, can arise mainly from the entropy balance of collective thermal modes, without conformational changes, is by now well known. However, the propensity to generate negative cooperativity is still unclear. Starting from an elastic-network picture of small protein complexes, in which effector binding is modeled by locally altering interaction strengths in lieu of adding a node-spring pair, we elucidate mechanisms particularly for such negative cooperativity. The approach via a few coupled harmonic oscillators with internal elastic strengths allows us to trace individual eigenmodes, their frequencies, and their statistical weights through successive bindings. We find that the alteration of the oscillators' couplings is paramount to covering both signs of allostery. Binding-modified couplings create a rich set of eigenmodes individually for each binding state, modes inaccessible to an ensemble of noninteracting units. The associated shifts of collective-mode frequencies, nonuniform with respect to modes and binding states, result in an enhanced optimizability, reflected by a subtle phase map of allosteric behaviors.


Assuntos
Entropia , Proteínas/química , Regulação Alostérica , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas/metabolismo
8.
Adv Exp Med Biol ; 1163: 1-23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707697

RESUMO

Allosteric regulation is a ubiquitous strategy employed in nature to control cellular processes by regulating the affinities of biomolecules. Allosteric modulators are able to tune the protein/substrate affinity in a highly predictable way, suggesting that such modulators may represent safe drugs. Tremendous advances have been made in the development of allosteric modulators and the characterization of their therapeutic targets. Here, we briefly introduce several representative allosteric modulators of important drug targets, such as the G protein-coupled receptor family. We also review the state-of-the-art experimental and computational approaches used in allosteric drug development. The accumulated knowledge of allosteric regulation and the technical progress made in drug development will lead to an explosion of promising allosteric drugs in the near future.


Assuntos
Desenvolvimento de Medicamentos , Regulação Alostérica , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Desenvolvimento de Medicamentos/tendências , Humanos
9.
Adv Exp Med Biol ; 1163: 25-43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707698

RESUMO

Allostery is largely associated with conformational and functional transitions in individual proteins. All dynamic proteins are allosteric. This concept can be extended to consider the impact of conformational perturbations on cellular function and disease states. In this section, we will illuminate how allostery can control physiological activities and cause disease, aiming to increase the awareness of the linkage between disease symptoms on the cellular level and specific aberrant allosteric actions on the molecular level.


Assuntos
Doença , Proteínas , Regulação Alostérica , Conformação Proteica , Proteínas/química , Transdução de Sinais
10.
Adv Exp Med Biol ; 1163: 65-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707700

RESUMO

An allosteric mechanism refers to the biological regulation process wherein macromolecules propagate the effect of ligand binding at one site to a spatially distant orthosteric locus, thus affecting activity. The theory has remained a trending topic in biology research for over 50 years, since the understanding of allostery is fundamental for gleaning numerous biological processes and developing new drug therapies. In the past two decades, the allosteric paradigm has evolved into more descriptive models, with ever-expanding amounts of experimental data pertaining to newly identified allosteric molecules. The AlloSteric Database (ASD, accessible at http://mdl.shsmu.edu.cn/ASD ), which is a comprehensive knowledge repository, has provided the public with integrated information encompassing allosteric proteins, modulators, sites, pathways, and networks to investigate allostery since 2009. In this chapter, we introduce the history and usage of the ASD and give attention to specific applications that have benefited from the ASD.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Proteínas , Regulação Alostérica , Bases de Dados de Proteínas , Descoberta de Drogas/tendências , Proteínas/química
11.
Adv Exp Med Biol ; 1163: 89-105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707701

RESUMO

Correlation between an allosteric site and its orthosteric site refers to the phenomenon that perturbations like ligand binding, mutation, or posttranslational modifications at the allosteric site leverage variation in the orthosteric site. Understanding this kind of correlation not only helps to disclose how information is transmitted in allosteric regulation but also provides clues for allosteric drug discovery. This chapter starts with an overview of correlation studies on allosteric and orthosteric sites and then introduces recent progress in evolutionary and simulation-based dynamic studies. Discussions and perspectives on future directions are also given.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Proteínas , Relação Estrutura-Atividade , Regulação Alostérica , Sítios de Ligação , Simulação por Computador , Proteínas/química , Proteínas/genética
12.
Adv Exp Med Biol ; 1163: 107-139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707702

RESUMO

Allostery is considered one of the most direct and efficient ways to regulate biological macromolecule functions. Allostery is increasingly receiving attention in the field of drug discovery because of the unique advantages of allosteric modulators such as high selectivity and low toxicity. Because of technical breakthroughs in the allosteric studies, the understanding of the characteristics of allosteric entities such as allosteric proteins and their allosteric sites and modulators has made great strides. These features play a critical role in both the evolution of the allosteric concept and the prediction of allosteric interactions. In this chapter, we highlight the fundamental characteristics of allosteric proteins, allosteric sites, and allosteric modulators. Importantly, the applications of such principles in real cases are depicted in detail. Collectively, these characteristics are beneficial in aiding allosteric drug design and allosteric mechanism research.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Proteínas , Regulação Alostérica , Proteínas/química
13.
Adv Exp Med Biol ; 1163: 141-169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707703

RESUMO

With the increasing difficulty to develop new drugs and the emergence of resistance to traditional orthosteric-site inhibitors, the search for alternatives is finally approaching the focus on allosteric sites. Allosteric sites offer opportunities to regulate many pharmacologically targeted pathways by inhibition or activation. In addition, allosteric sites tend to be less conserved than the functional site, which may facilitate the design of specific effectors in the protein families for which specific orthosteric inhibitors have proved difficult to design. Furthermore, recent evidence suggests that all proteins might be susceptible of allosteric regulation, increasing the space of druggable targets. Computational identification of allosteric sites has therefore become an active field of research. The problem can be approached from two sides: (1) the identification of allosteric-communication pathways between the functional site and potential allosteric sites and (2) the functional-site-independent identification of allosteric sites. While the first approach tends to be more laborious and thus restricted to a single protein, the second tends to be more amenable to larger-scale analysis, thus providing tools for the two drug discovery scenarios: the analysis of known targets and the screening for new potential targets. Here, I show some basic concepts and methods useful to the identification of allosteric sites and pathways, in line with these two approaches. I describe them in some detail to build a clear framework, at the risk of losing the interest of experts. Examples of recent studies involving these methods are also illustrated, focusing on the techniques rather than on their findings on allosterism.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Proteínas , Regulação Alostérica , Descoberta de Drogas/tendências , Proteínas/química
14.
Adv Exp Med Biol ; 1163: 171-186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707704

RESUMO

NMR allows assessment of protein structure in solution. Unlike conventional X-ray crystallography that provides snapshots of protein conformations, all conformational states are simultaneously accessible to analysis by NMR. This is a significant advantage for discovery and characterization of allosteric effects. These effects are observed when binding at one site of the protein affects another distinct site through conformational transitions. Allosteric regulation of proteins has been observed in multiple physiological processes in health and disease, providing an opportunity for the development of allosteric inhibitors. These compounds do not directly interact with the orthosteric site of the protein but influence its structure and function. In this book chapter, we provide an overview on how NMR methods are utilized to identify allosteric sites and to discover novel inhibitors, highlighting examples from the field. We also describe how NMR has contributed to understanding of allosteric mechanisms and propose that it is likely to play an important role in clarification and further development of key concepts of allostery.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Ligantes , Espectroscopia de Ressonância Magnética , Regulação Alostérica , Sítios de Ligação , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Conformação Proteica
15.
Adv Exp Med Biol ; 1163: 187-223, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707705

RESUMO

Computational studies of allosteric interactions have witnessed a recent renaissance fueled by the growing interest in modeling of the complex molecular assemblies and biological networks. Allosteric interactions in protein structures allow for molecular communication in signal transduction networks. In this chapter, we discuss recent developments in understanding of allosteric mechanisms and interactions of protein systems, particularly in the context of structural, functional, and computational studies of allosteric inhibitors and activators. Computational and experimental approaches and advances in understanding allosteric regulatory mechanisms are reviewed to provide a systematic and critical view of the current progress in the development of allosteric modulators and highlight most challenging questions in the field. The abundance and diversity of genetic, structural, and biochemical data underlies the complexity of mechanisms by which targeted and personalized drugs can combat mutational profiles in protein kinases. Structural and computational studies of protein kinases have generated in recent decade significant insights that allowed leveraging knowledge about conformational diversity and allosteric regulation of protein kinases in the design and discovery of novel kinase drugs. We discuss recent developments in understanding multilayered allosteric regulatory machinery of protein kinases and provide a systematic view of the current state in understanding molecular basis of allostery mediated by kinase inhibitors and activators. In conclusion, we highlight the current status and future prospects of computational biology approaches in bridging the basic science of protein kinases with the discovery of anticancer therapies.


Assuntos
Regulação Alostérica , Biologia Computacional , Mapas de Interação de Proteínas , Inibidores de Proteínas Quinases , Proteínas Quinases , Transdução de Sinais , Regulação Alostérica/efeitos dos fármacos , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Adv Exp Med Biol ; 1163: 225-251, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707706

RESUMO

G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology; about one-third of all marketed drugs target members of this family. GPCR allosteric ligands hold the promise of improved subtype selectivity, spatiotemporal sensitivity, and possible biased property over typical orthosteric ligands. However, only a small number of GPCR allosteric ligands have been approved as drugs or in clinical trials since the discovery process is very challenging. The rapid development of GPCR structural biology leads to the discovery of several allosteric sites and sheds light on understanding the mechanism of GPCR allosteric ligands, which is critical for discovering novel therapeutics. This book chapter summarized different GPCR allosteric modulating mechanisms and discussed validated mechanisms based on allosteric modulator-GPCR complex structures.


Assuntos
Descoberta de Drogas , Receptores Acoplados a Proteínas-G , Regulação Alostérica , Sítio Alostérico , Humanos , Ligantes , Relação Estrutura-Atividade
17.
Adv Exp Med Biol ; 1163: 253-278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707707

RESUMO

Deregulation of protein kinase activity has been linked to many diseases ranging from cancer to AIDS and neurodegenerative diseases. Not surprisingly, drugging the human kinome - the complete set of kinases encoded by the human genome - has been one of the major drug discovery pipelines. Majority of the approved clinical kinase inhibitors target the ATP binding site of kinases. However, the remarkable sequence and structural similarity of ATP binding pockets of kinases make selective inhibition of kinases a daunting task. To circumvent these issues, allosteric inhibitors that target sites other than the orthosteric ATP binding pocket have been developed. The structural diversity of the allosteric sites allows these inhibitors to have higher selectivity, lower toxicity and improved physiochemical properties and overcome drug resistance associated with the use of conventional kinase inhibitors. In this chapter, we will focus on the allosteric inhibitors of selected serine/threonine kinases, outline the benefits of using these inhibitors and discuss the challenges and future opportunities.


Assuntos
Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo
18.
Adv Exp Med Biol ; 1163: 279-311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707708

RESUMO

Allostery is a basic principle that enables proteins to process and transmit cellular information. Protein kinases evolved allosteric mechanisms to transduce cellular signals to downstream signalling components or effector molecules. Protein kinases catalyse the transfer of the terminal phosphate from ATP to protein substrates upon specific stimuli. Protein kinases are targets for the development of small molecule inhibitors for the treatment of human diseases. Drug development has focussed on ATP-binding site, while there is increase interest in the development of drugs targeting alternative sites, i.e. allosteric sites. Here, we review the mechanism of regulation of protein kinases, which often involve the allosteric modulation of the ATP-binding site, enhancing or inhibiting activity. We exemplify the molecular mechanism of allostery in protein kinases downstream of PI3-kinase signalling with a focus on phosphoinositide-dependent protein kinase 1 (PDK1), a model kinase where small compounds can allosterically modulate the conformation of the kinase bidirectionally.


Assuntos
Desenvolvimento de Medicamentos , Fosfatidilinositol 3-Quinases , Proteínas Quinases , Transdução de Sinais , Regulação Alostérica , Sítio Alostérico , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Adv Exp Med Biol ; 1163: 313-334, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707709

RESUMO

Protein-protein interactions (PPIs) represent promising drug targets of broad-spectrum therapeutic interests due to their critical implications in both health and disease circumstances. Hence, they are widely accepted as the Holy Grail of drug development. Historically, PPIs were rendered "undruggable" for their large, flat, and pocket-less structures. Current attempts to drug these "intractable" targets include orthosteric and allosteric methodologies. Previous efforts employing orthosteric approaches like protein therapeutics and orthosteric small molecules frequently suffered from poor performance caused by the difficulties in directly targeting PPI interfaces. As structural biology progresses rapidly, allosteric modulators, which direct to the allosteric regulatory sites remote to the PPI surfaces, have gradually established as a potential solution. Allosteric pockets are topologically distal from the PPI orthosteric sites, and their ligands do not need to compete with the PPI partners, which helps to improve the physiochemical and pharmacological properties of allosteric PPI modulators. Thus, exploiting allostery to tailor PPIs is regarded as a tempting strategy in future PPI drug discovery. Here, we provide a comprehensive review of our representative achievements along the way we utilize allosteric effects to tame the difficult PPI systems into druggable targets. Importantly, we provide an in-depth mechanistic analysis of this success, which will be instructive to future related lead optimizations and drug design. Finally, we discuss the current challenges in allosteric PPI drug discovery. Their solutions as well as future perspectives are also presented.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Regulação Alostérica , Sítio Alostérico/fisiologia , Ligantes , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia
20.
Adv Exp Med Biol ; 1163: 335-357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707710

RESUMO

The allosteric property of globular proteins is applauded as their intrinsic ability to regulate distant sites, and this property further plays a critical role in a wide variety of cellular regulatory mechanisms. Recent advancements and studies have revealed the manifestation of allostery in intrinsically disordered proteins or regions as allosteric sites present within or mediated by IDP/IDRs facilitates the signaling interactions for various biological mechanisms which would otherwise be impossible for globular proteins to regulate. This thematic review has highlighted the biological outcomes that can be achieved by the mechanism of allosteric regulation of intrinsically disordered proteins or regions. The similar mechanism has been implemented on Adenovirus 5 early region 1A and tumor apoptosis protein p53 in correspondence with other partners in binary and ternary complexes, which are the subject of the current review. Both these proteins regulate once they bind to their partners, consequently, forming either a binary or a ternary complex. Allosteric regulation by IDPs is currently a subject undergoing intense study, and the ongoing research work will ensure a better understanding of precision and efficiency of cellular regulation by them. Allosteric regulation mechanism can also be researched by intrinsically disordered protein-specific force field.


Assuntos
Proteínas Intrinsicamente Desordenadas , Regulação Alostérica , Proteínas Intrinsicamente Desordenadas/química , Ligação Proteica , Transdução de Sinais
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