scholarly journals Communication pathways bridge local and global conformations in an IgG4 antibody

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thomas Tarenzi ◽  
Marta Rigoli ◽  
Raffaello Potestio
Keyword(s):  
Conformational Changes ◽  
Md Simulations ◽  
Specific Sequence ◽  
Multi Scale ◽  
Complementarity Determining Regions ◽  
Global And Local ◽  
Cell Death Protein ◽  
Antibody Function ◽  
Scale Hierarchy ◽  
Igg4 Antibody

AbstractThe affinity of an antibody for its antigen is primarily determined by the specific sequence and structural arrangement of the complementarity-determining regions (CDRs). Recent evidence, however, points toward a nontrivial relation between the CDR and distal sites: variations in the binding strengths have been observed upon mutating residues separated from the paratope by several nanometers, thus suggesting the existence of a communication network within antibodies, whose extension and relevance might be deeper than insofar expected. In this work, we test this hypothesis by means of molecular dynamics (MD) simulations of the IgG4 monoclonal antibody pembrolizumab, an approved drug that targets the programmed cell death protein 1 (PD-1). The molecule is simulated in both the apo and holo states, totalling 4 μs of MD trajectory. The analysis of these simulations shows that the bound antibody explores a restricted range of conformations with respect to the apo one, and that the global conformation of the molecule correlates with that of the CDR. These results support the hypothesis that pembrolizumab featues a multi-scale hierarchy of intertwined global and local conformational changes. The analysis pipeline developed in this work is general, and it can help shed further light on the mechanistic aspects of antibody function.

scholarly journals How Communication Pathways Bridge Local and Global Conformations in an IgG4 Antibody: a Molecular Dynamics Study

2021 ◽  
Author(s):  
Thomas Tarenzi ◽  
Marta Rigoli ◽  
Raffaello Potestio
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Md Simulations ◽  
Specific Sequence ◽  
Multi Scale ◽  
Antibody Structure ◽  
Complementarity Determining Regions ◽  
Global And Local ◽  
Cell Death Protein ◽  
Antibody Function

The affinity of an antibody for its antigen is primarily determined by the specific sequence and structural arrangement of the complementarity-determining regions (CDRs). Recently, however, evidence has accumulated that points toward a nontrivial relation between the CDR and distal sites on the antibody structure: variations in the binding strengths have been observed upon mutating amino acids separated from the paratope by several nanometers, thus suggesting the existence of a communication network within antibodies whose extension and relevance might be deeper than insofar expected. In this work, we test this hypothesis by means of molecular dynamics (MD) simulations of the IgG4 monoclonal antibody pembrolizumab, an approved drug that targets the programmed cell death protein 1 (PD-1). The molecule is simulated in both the apo and holo states, totalling 4 μs of MD trajectory. The analysis of these simulations shows that the bound antibody explores a restricted range of conformations with respect to the apo one, and that the global conformation of the molecule correlates with that of the CDR; a pivotal role in this relationship is played by the relatively short hinge, which mechanically couples Fab and Fc domains. These results support the hypothesis that pembrolizumab behaves as a complex machinery, with a multi-scale hierarchy of global and local conformational changes that communicate with one another. The analysis pipeline developed in this work is general, and it can help shed further light on the mechanistic aspects of antibody function.

Closing the gap: an atomistic structural and functional perspective of S. mansoni universal stress G4LZI3 protein in complex with phenolic compounds

2020 ◽  
Vol 17 ◽  
Author(s):  
Priscilla Masamba ◽  
Geraldene Munsamy ◽  
Abidemi Paul Kappo
Keyword(s):  
Phenolic Compounds ◽  
Conformational Changes ◽  
Stress Protein ◽  
Md Simulations ◽  
Binding Energies ◽  
Developmental Cycle ◽  
Structure Based Drug Design ◽  
Bioinformatic Tools ◽  
Drug Of Choice ◽  
Functional Perspective

Background: For decades, Praziquantel has been the undisputed drug of choice for all schistosome infections, but rising concerns due to the unelucidated mechanism of action of the drug and unavoidable reports of emerging drug resistant strains has necessitated the need for alternative treatment drug. Moreover, current apprehension has been reinforced by total dependence on the drug for treatment hence, the search for novel and effective anti-schistosomal drugs. Uses: This study made use of bioinformatic tools to determine the structural binding of the Universal G4LZI3 stress protein (USP) in complex with ten polyphenol compounds, thereby highlighting the effectiveness of these recently identified ‘lead’ molecules in the design of novel therapeutics targeted against schistosomiasis. Upregulation of the G4LZI3 USP throughout the schistosome multifaceted developmental cycle sparks interest in its potential role as a druggable target. The integration of in silico tools provides an atomistic perspective into the binding of potential inhibitors to target proteins. Conclusion: This study therefore, implemented the use of molecular dynamic (MD) simulations to provide functional and structural insight into key conformational changes upon binding of G4ZLI3 to these key phenolic compounds. Post-MD analyses revealed unique structural and conformational changes in the G4LZI3 protein in complex with curcumin and catechin respectively. These systems exhibited the highest binding energies, while the major interacting residues conserved in all the complexes provides a route map for structure-based drug design of novel compounds with enhanced inhibitory potency against the G4LZI3 protein. This study suggests an alternative approach for the development of anti-schistosomal drugs using natural compounds.

scholarly journals Correlation of membrane protein conformational and functional dynamics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Raghavendar Reddy Sanganna Gari ◽  
Joel José Montalvo‐Acosta ◽  
George R. Heath ◽  
Yining Jiang ◽  
Xiaolong Gao ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Conformational Changes ◽  
Single Channel ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
High Temporal Resolution ◽  
Dependent Manner ◽  
Functional Dynamics ◽  
Ph Dependent ◽  
Open States

AbstractConformational changes in ion channels lead to gating of an ion-conductive pore. Ion flux has been measured with high temporal resolution by single-channel electrophysiology for decades. However, correlation between functional and conformational dynamics remained difficult, lacking experimental techniques to monitor sub-millisecond conformational changes. Here, we use the outer membrane protein G (OmpG) as a model system where loop-6 opens and closes the β-barrel pore like a lid in a pH-dependent manner. Functionally, single-channel electrophysiology shows that while closed states are favored at acidic pH and open states are favored at physiological pH, both states coexist and rapidly interchange in all conditions. Using HS-AFM height spectroscopy (HS-AFM-HS), we monitor sub-millisecond loop-6 conformational dynamics, and compare them to the functional dynamics from single-channel recordings, while MD simulations provide atomistic details and energy landscapes of the pH-dependent loop-6 fluctuations. HS-AFM-HS offers new opportunities to analyze conformational dynamics at timescales of domain and loop fluctuations.

scholarly journals Single image super resolution based on multi-scale structure and non-local smoothing

2021 ◽  
Vol 2021 (1) ◽  
Author(s):  
Wenyi Wang ◽  
Jun Hu ◽  
Xiaohong Liu ◽  
Jiying Zhao ◽  
Jianwen Chen
Keyword(s):  
Super Resolution ◽  
Principal Component ◽  
Feature Mapping ◽  
Multi Scale ◽  
Non Local ◽  
Image Super Resolution ◽  
Gaussian Blur ◽  
Single Image Super Resolution ◽  
Global And Local ◽  
Bicubic Interpolation

AbstractIn this paper, we propose a hybrid super-resolution method by combining global and local dictionary training in the sparse domain. In order to present and differentiate the feature mapping in different scales, a global dictionary set is trained in multiple structure scales, and a non-linear function is used to choose the appropriate dictionary to initially reconstruct the HR image. In addition, we introduce the Gaussian blur to the LR images to eliminate a widely used but inappropriate assumption that the low resolution (LR) images are generated by bicubic interpolation from high-resolution (HR) images. In order to deal with Gaussian blur, a local dictionary is generated and iteratively updated by K-means principal component analysis (K-PCA) and gradient decent (GD) to model the blur effect during the down-sampling. Compared with the state-of-the-art SR algorithms, the experimental results reveal that the proposed method can produce sharper boundaries and suppress undesired artifacts with the present of Gaussian blur. It implies that our method could be more effect in real applications and that the HR-LR mapping relation is more complicated than bicubic interpolation.

Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications

2015 ◽  
Vol 43 (5) ◽  
pp. 1023-1032 ◽  
Author(s):  
Thomas Stockner ◽  
Anna Mullen ◽  
Fraser MacMillan
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Epr Spectroscopy ◽  
Structural Information ◽  
Dynamic Properties ◽  
Molecular System ◽  
Synergistic Effects ◽  
Md Simulations ◽  
Substrate Spectrum

ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented.

THEORETICAL INVESTIGATIONS ON ELUCIDATING FUNDAMENTAL MECHANISMS OF CATALYSIS AND DYNAMICS INVOLVED IN TRANSCRIPTION BY RNA POLYMERASE

2013 ◽  
Vol 12 (08) ◽  
pp. 1341005 ◽  
Author(s):  
FÁTIMA PARDO-AVILA ◽  
LIN-TAI DA ◽  
YING WANG ◽  
XUHUI HUANG
Keyword(s):  
Rna Polymerase ◽  
Conformational Changes ◽  
Normal Mode Analysis ◽  
Md Simulations ◽  
Mode Analysis ◽  
Transcription Process ◽  
Nucleotide Addition ◽  
Theoretical Investigations ◽  
State Models ◽  
Elongation Process

RNA polymerase is the enzyme that synthesizes RNA during the transcription process. To understand its mechanism, structural studies have provided us pictures of the series of steps necessary to add a new nucleotide to the nascent RNA chain, the steps altogether known as the nucleotide addition cycle (NAC). However, these static snapshots do not provide dynamic information of these processes involved in NAC, such as the conformational changes of the protein and the atomistic details of the catalysis. Computational studies have made efforts to fill these knowledge gaps. In this review, we provide examples of different computational approaches that have improved our understanding of the transcription elongation process for RNA polymerase, such as normal mode analysis, molecular dynamic (MD) simulations, Markov state models (MSMs). We also point out some unsolved questions that could be addressed using computational tools in the future.

scholarly journals Multi-scale Method for the Crack Problem in Microstructural Materials

2010 ◽  
Vol 10 (1) ◽  
pp. 69-86 ◽  
Author(s):  
R. H. W. Hoppe ◽  
S.I. Petrova
Keyword(s):  
Finite Element ◽  
Crack Problem ◽  
Material Model ◽  
Superposition Method ◽  
The Finite Element Method ◽  
Multi Scale ◽  
Microscopic Models ◽  
Modeling Strategy ◽  
Porous Microstructures ◽  
Global And Local

AbstractThe paper deals with the numerical computation of a crack problem posed on microstructural heterogeneous materials containing multiple phases in the microstructure. The failure of such materials is a natural multi-scale effect since cracks typically nucleate in regions of defects on the microscopic scale. The modeling strategy for solving the crack problem concerns simultaneously the macroscopic and microscopic models. Our approach is based on an efficient combination of the homogenization technique and the mesh superposition method (s-version of the finite element method). The homogenized model relies on a double-scale asymptotic expansion of the displacement field. The mesh superposition method uses two independent (global and local) finite element meshes and the concept of superposing the local mesh arbitrarily on the global continuous mesh. The crack is treated by the local mesh and the homogenized material model is considered on the global mesh. Numerical experiments for problems on biomorphic microcellular ceramic templates with porous microstructures of different materials constituents are presented.

scholarly journals Cu2+-based distance measurements by pulsed EPR provide distance constraints for DNA backbone conformations in solution

2020 ◽  
Vol 48 (9) ◽  
pp. e49-e49 ◽  
Author(s):  
Shreya Ghosh ◽  
Matthew J Lawless ◽  
Hanna J Brubaker ◽  
Kevin Singewald ◽  
Michael R Kurpiewski ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Conformational Changes ◽  
Continuous Wave ◽  
Md Simulations ◽  
Distance Measurements ◽  
Paramagnetic Resonance ◽  
Pulsed Epr ◽  
Distance Distributions ◽  
Dna Backbone ◽  
Double Electron Electron Resonance

Abstract Electron paramagnetic resonance (EPR) has become an important tool to probe conformational changes in nucleic acids. An array of EPR labels for nucleic acids are available, but they often come at the cost of long tethers, are dependent on the presence of a particular nucleotide or can be placed only at the termini. Site directed incorporation of Cu2+-chelated to a ligand, 2,2′dipicolylamine (DPA) is potentially an attractive strategy for site-specific, nucleotide independent Cu2+-labelling in DNA. To fully understand the potential of this label, we undertook a systematic and detailed analysis of the Cu2+-DPA motif using EPR and molecular dynamics (MD) simulations. We used continuous wave EPR experiments to characterize Cu2+ binding to DPA as well as optimize Cu2+ loading conditions. We performed double electron-electron resonance (DEER) experiments at two frequencies to elucidate orientational selectivity effects. Furthermore, comparison of DEER and MD simulated distance distributions reveal a remarkable agreement in the most probable distances. The results illustrate the efficacy of the Cu2+-DPA in reporting on DNA backbone conformations for sufficiently long base pair separations. This labelling strategy can serve as an important tool for probing conformational changes in DNA upon interaction with other macromolecules.

scholarly journals Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

2020 ◽  
Vol 21 (6) ◽  
pp. 2167
Author(s):  
Jingxuan Zhu ◽  
Congcong Li ◽  
Hengzheng Yang ◽  
Xiaoqing Guo ◽  
Tianci Huang ◽  
...  
Keyword(s):  
Molecular Dynamic ◽  
Conformational Changes ◽  
Computational Study ◽  
Md Simulations ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Lung Cancers ◽  
Mitogen Activated Protein ◽  
Alk Positive

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

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