NMR Approaches To Understanding Protein Specificity

1997 ◽  
Author(s):  
G.C. K. Roberts ◽  
L.-Y. Lian
Keyword(s):  
Nmr Spectroscopy ◽  
Ligand Binding ◽  
Pathogenic Bacteria ◽  
Structural Information ◽  
Nuclear Overhauser Effect ◽  
Protein Protein Interactions ◽  
Ligand Complex ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Nuclear Overhauser

The biological functions of proteins all depend on their highly specific interactions with other molecules, and the understanding of the molecular basis of the specificity of these interactions is an important part of the effort to understand protein structure-function relationships. NMR spectroscopy can provide information on many different aspects of protein-ligand interactions, ranging from the determination of the complete structure of a protein-ligand complex to focussing on selected features of the interactions between the ligand and protein by using “reporter groups” on the ligand or the protein. It has two particular advantages: the ability to study the complex in solution, and the ability to provide not only structural, but also dynamic, kinetic and thermodynamic information on ligand binding. Early analyses of ligand binding (Jardetzky and Roberts, 1981) focused on measurements of relaxation times, chemical shifts and coupling constants, which gave relatively limited, although valuable, structural information. More recently, it has become possible to obtain much more detailed information, due to the extensive use of nuclear Overhauser effect measurements and isotope-labeled proteins and ligands; a number of reviews of this area are available (Feeney and Birdsall, 1993; Lian et al, 1994; Wand and Short, 1994; Petros and Fesik, 1994; Wemmer and Williams, 1994). In this article, we describe some recent work from our laboratory which illustrates the use of NMR spectroscopy to obtain structural and mechanistic information on relatively large enzyme-substrate and proteinprotein complexes. A number of species of pathogenic bacteria, notably Streptococci and Staphylococci, have proteins on their surface that bind immurioglobulins (reviewed in Boyle (1990)). Protein A from S. aureus and protein G from species of Streptococci are widely used as imrnunological tools and are the most extensively studied of these antibody-binding proteins. A detailed understanding of the binding mechanisms of these proteins is important, not only for providing us with the structural basis for their functions, but also as a contribution toward understanding the general rules of protein-protein interactions.

Combiphore (Structure and Ligand Based Pharmacophore) - Approach for the Design of GPR40 Modulators in the Management of Diabetes

2020 ◽  
Vol 17 (2) ◽  
pp. 233-247
Author(s):  
Krishna A. Gajjar ◽  
Anuradha K. Gajjar
Keyword(s):  
Molecular Docking ◽  
Structural Information ◽  
Docking Studies ◽  
Structural Motif ◽  
Roc Curve Analysis ◽  
Ligand Complex ◽  
Discovery Studio ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Pharmacophore Models

Background: Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators. Methods: DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software. Results and Conclusion: Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study.

scholarly journals Layer-wise relevance propagation of InteractionNet explains protein–ligand interactions at the atom level

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hyeoncheol Cho ◽  
Eok Kyun Lee ◽  
Insung S. Choi
Keyword(s):  
Dissociation Constants ◽  
Structural Information ◽  
Three Dimensional ◽  
Graph Representation ◽  
Ligand Complex ◽  
Covalent Bonds ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Atom Level ◽  
Graph Neural Networks

AbstractDevelopment of deep-learning models for intermolecular noncovalent (NC) interactions between proteins and ligands has great potential in the chemical and pharmaceutical tasks, including structure–activity relationship and drug design. It still remains an open question how to convert the three-dimensional, structural information of a protein–ligand complex into a graph representation in the graph neural networks (GNNs). It is also difficult to know whether a trained GNN model learns the NC interactions properly. Herein, we propose a GNN architecture that learns two distinct graphs—one for the intramolecular covalent bonds in a protein and a ligand, and the other for the intermolecular NC interactions between the protein and the ligand—separately by the corresponding covalent and NC convolutional layers. The graph separation has some advantages, such as independent evaluation on the contribution of each convolutional step to the prediction of dissociation constants, and facile analysis of graph-building strategies for the NC interactions. In addition to its prediction performance that is comparable to that of a state-of-the art model, the analysis with an explainability strategy of layer-wise relevance propagation shows that our model successfully predicts the important characteristics of the NC interactions, especially in the aspect of hydrogen bonding, in the chemical interpretation of protein–ligand binding.

scholarly journals A Practical Perspective on the Roles of Solution NMR Spectroscopy in Drug Discovery

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 2974
Author(s):  
Qingxin Li ◽  
CongBao Kang
Keyword(s):  
Drug Discovery ◽  
Nmr Spectroscopy ◽  
Ligand Binding ◽  
Conformational Changes ◽  
Solution Nmr ◽  
Binding Modes ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Solution Nmr Spectroscopy ◽  
Solution Nuclear Magnetic Resonance

Solution nuclear magnetic resonance (NMR) spectroscopy is a powerful tool to study structures and dynamics of biomolecules under physiological conditions. As there are numerous NMR-derived methods applicable to probe protein–ligand interactions, NMR has been widely utilized in drug discovery, especially in such steps as hit identification and lead optimization. NMR is frequently used to locate ligand-binding sites on a target protein and to determine ligand binding modes. NMR spectroscopy is also a unique tool in fragment-based drug design (FBDD), as it is able to investigate target-ligand interactions with diverse binding affinities. NMR spectroscopy is able to identify fragments that bind weakly to a target, making it valuable for identifying hits targeting undruggable sites. In this review, we summarize the roles of solution NMR spectroscopy in drug discovery. We describe some methods that are used in identifying fragments, understanding the mechanism of action for a ligand, and monitoring the conformational changes of a target induced by ligand binding. A number of studies have proven that 19F-NMR is very powerful in screening fragments and detecting protein conformational changes. In-cell NMR will also play important roles in drug discovery by elucidating protein-ligand interactions in living cells.

Investigation of the structure of regulatory proteins interacting with glycosaminoglycans by combining NMR spectroscopy and molecular modeling – the beginning of a wonderful friendship

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Georg Künze ◽  
Daniel Huster ◽  
Sergey A. Samsonov
Keyword(s):  
Nmr Spectroscopy ◽  
Structural Information ◽  
Md Simulations ◽  
Specific Protein ◽  
Regulatory Proteins ◽  
Structural Constraints ◽  
Modeling Tools ◽  
Nuclear Overhauser ◽  
Nmr Methods ◽  
High Flexibility

Abstract The interaction of regulatory proteins with extracellular matrix or cell surface-anchored glycosaminoglycans (GAGs) plays important roles in molecular recognition, wound healing, growth, inflammation and many other processes. In spite of their high biological relevance, protein-GAG complexes are significantly underrepresented in structural databases because standard tools for structure determination experience difficulties in studying these complexes. Co-crystallization with subsequent X-ray analysis is hampered by the high flexibility of GAGs. NMR spectroscopy experiences difficulties related to the periodic nature of the GAGs and the sparse proton network between protein and GAG with distances that typically exceed the detection limit of nuclear Overhauser enhancement spectroscopy. In contrast, computer modeling tools have advanced over the last years delivering specific protein-GAG docking approaches successfully complemented with molecular dynamics (MD)-based analysis. Especially the combination of NMR spectroscopy in solution providing sparse structural constraints with molecular docking and MD simulations represents a useful synergy of forces to describe the structure of protein-GAG complexes. Here we review recent methodological progress in this field and bring up examples where the combination of new NMR methods along with cutting-edge modeling has yielded detailed structural information on complexes of highly relevant cytokines with GAGs.

Using molecular docking and molecular dynamics to investigate protein-ligand interactions

2021 ◽  
Vol 35 (08) ◽  
pp. 2130002
Author(s):  
Connor J. Morris ◽  
Dennis Della Corte
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Drug Discovery ◽  
State Of The Art ◽  
Ligand Complex ◽  
Protein Ligand Interactions ◽  
Art Methods ◽  
Ligand Interactions ◽  
Docking Calculations ◽  
Ligand Bond

Molecular docking and molecular dynamics (MD) are powerful tools used to investigate protein-ligand interactions. Molecular docking programs predict the binding pose and affinity of a protein-ligand complex, while MD can be used to incorporate flexibility into docking calculations and gain further information on the kinetics and stability of the protein-ligand bond. This review covers state-of-the-art methods of using molecular docking and MD to explore protein-ligand interactions, with emphasis on application to drug discovery. We also call for further research on combining common molecular docking and MD methods.

Improving protein–ligand binding prediction by considering the bridging water molecules in Autodock

2019 ◽  
Vol 18 (05) ◽  
pp. 1950027 ◽  
Author(s):  
Qiangna Lu ◽  
Lian-Wen Qi ◽  
Jinfeng Liu
Keyword(s):  
Ligand Binding ◽  
Considerable Improvement ◽  
Ligand Docking ◽  
Water Molecules ◽  
Binding Modes ◽  
Binding Prediction ◽  
Docking Simulations ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Docking Program

Water plays a significant role in determining the protein–ligand binding modes, especially when water molecules are involved in mediating protein–ligand interactions, and these important water molecules are receiving more and more attention in recent years. Considering the effects of water molecules has gradually become a routine process for accurate description of the protein–ligand interactions. As a free docking program, Autodock has been most widely used in predicting the protein–ligand binding modes. However, whether the inclusion of water molecules in Autodock would improve its docking performance has not been systematically investigated. Here, we incorporate important bridging water molecules into Autodock program, and systematically investigate the effectiveness of these water molecules in protein–ligand docking. This approach was evaluated using 18 structurally diverse protein–ligand complexes, in which several water molecules bridge the protein–ligand interactions. Different treatment of water molecules were tested by using the fixed and rotatable water molecules, and a considerable improvement in successful docking simulations was found when including these water molecules. This study illustrates the necessity of inclusion of water molecules in Autodock docking, and emphasizes the importance of a proper treatment of water molecules in protein–ligand binding predictions.

scholarly journals Correction: 19F multiple-quantum coherence NMR spectroscopy for probing protein–ligand interactions

RSC Advances ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 3503-3503
Author(s):  
Anna Zawadzka-Kazimierczuk ◽  
Mate Somlyay ◽  
Hanspeter Kaehlig ◽  
George Iakobson ◽  
Petr Beier ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Quantum Coherence ◽  
Multiple Quantum ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Multiple Quantum Coherence

Correction for ‘19F multiple-quantum coherence NMR spectroscopy for probing protein–ligand interactions’ by Anna Zawadzka-Kazimierczuk et al., RSC Adv., 2018, 8, 40687–40692.

scholarly journals Designing interactions by control of protein–ligand complex conformation: tuning arginine–arene interaction geometry for enhanced electrostatic protein–ligand interactions

2018 ◽  
Vol 9 (4) ◽  
pp. 1014-1021 ◽  
Author(s):  
A.-L. Noresson ◽  
O. Aurelius ◽  
C. T. Öberg ◽  
O. Engström ◽  
A. P. Sundin ◽  
...  
Keyword(s):  
Protein Conformation ◽  
Salt Bridges ◽  
Ligand Complex ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Galectin 3 ◽  
Control Protein

3-Benzamido-2-O-sulfo-galactosides can be designed to control protein conformation into forming entropically favourable galectin-3-arginine salt bridges with ligand sulfates.

An evaluation of high resolution nuclear magnetic resonance experiments and protocols in the structure elucidation of organic molecules. I. A relatively simple system, brucine

1985 ◽  
Vol 63 (2) ◽  
pp. 483-490 ◽  
Author(s):  
Michael A. Bernstein ◽  
Laurance D. Hall
Keyword(s):  
High Resolution ◽  
Chemical Shift ◽  
Structural Information ◽  
Nuclear Overhauser Effect ◽  
Proton Spectrum ◽  
Nmr Spectrum ◽  
H Nmr ◽  
Overhauser Effect ◽  
Nuclear Overhauser ◽  
Nmr Methods

Using a combination of one-dimensional (1D) and two-dimensional (2D) high resolution nmr methods, the 1H nmr spectrum of brucine was fully assigned. The 2D J-resolved and homonuclear chemical shift correlated (COSY) experiments provided assignments without full structural information; this was obtained from nuclear Overhauser effect (nOe) enhancement experiments (1D and 2D). With the proton spectrum fully assigned, proton-bearing carbons in the 13C nmr spectrum were easily assigned using the 2D heteronuclear chemical shift correlation map (CSCM) experiment.

Sign in / Sign up

Export Citation Format

Share Document