scholarly journals Molecular Conformations of Di-, Tri-, and Tetra-α-(2→8)-Linked Sialic Acid from NMR Spectroscopy and MD Simulations

2019 ◽  
Vol 21 (1) ◽  
pp. 30
Author(s):  
Aysegül Turupcu ◽  
Markus Blaukopf ◽  
Paul Kosma ◽  
Chris Oostenbrink
Keyword(s):  
Sialic Acid ◽  
Nmr Spectroscopy ◽  
Structural Information ◽  
Sampling Technique ◽  
Md Simulations ◽  
Coupling Constants ◽  
Enhanced Sampling ◽  
Molecular Conformations ◽  
J Coupling ◽  
Dynamics Simulations

By using molecular dynamics simulations with an efficient enhanced sampling technique and in combination with nuclear magnetic resonance (NMR) spectroscopy quantitative structural information on α -2,8-linked sialic acids is presented. We used a bottom-up approach to obtain a set of larger ensembles for tetra- and deca-sialic acid from model dimer and trimer systems that are in agreement with the available J-coupling constants and nuclear Overhauser effects. The molecular dynamic (MD) simulations with enhanced sampling are used to validate the force field used in this study for its further use. This empowered us to couple NMR observables in the MD framework via J-coupling and distance restraining simulations to obtain conformations that are supported by experimental data. We used these conformations in thermodynamic integration and one-step perturbation simulations to calculate the free-energy of suggested helical conformations. This study brings most of the available NMR experiments together and supplies information to resolve the conflict on the structures of poly- α -2,8-linked sialic acid.

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.

Molecular Conformations in the Pentasaccharide LNF-1 Derived from NMR Spectroscopy and Molecular Dynamics Simulations

2011 ◽  
Vol 115 (21) ◽  
pp. 7109-7121 ◽  
Author(s):  
Elin Säwén ◽  
Baltzar Stevensson ◽  
Jennie Östervall ◽  
Arnold Maliniak ◽  
Göran Widmalm
Keyword(s):  
Molecular Dynamics ◽  
Nmr Spectroscopy ◽  
Molecular Dynamics Simulations ◽  
Molecular Conformations ◽  
Dynamics Simulations

The solution conformations of amino acids from molecular dynamics simulations of Gly-X-Gly peptides: comparison with NMR parameters

1998 ◽  
Vol 76 (2-3) ◽  
pp. 164-170 ◽  
Author(s):  
David van der Spoel
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Nuclear Magnetic Resonance ◽  
Magnetic Resonance ◽  
Chemical Shifts ◽  
Coupling Constants ◽  
Random Coil ◽  
J Coupling ◽  
Dynamics Simulations ◽  
Nuclear Magnetic

The conformations that amino acids can adopt in the random coil state are of fundamental interest in the context of protein folding research and studies of protein–peptide interactions. To date, no detailed quantitative data from experimental studies have been reported; only nuclear magnetic resonance parameters such as chemical shifts and J coupling constants have been reported. These experimental nuclear magnetic resonance data represent averages over multiple conformations, and hence they do not provide unique structural information. I have performed relatively long (2.5 ns) molecular dynamics simulations of Gly-X-Gly tripeptides, surrounded by explicit water molecules, where X represents eight different amino acids with long side chains. From the trajectories one can calculate time averaged backbone chemical shifts and 3JNHα coupling constants and compare these with experimental data. These calculated quantities are quite close to the experimental values for most amino acids, suggesting that these simulations are a good model for the random coil state of the tripeptides. On the basis of my simulations I predict 3Jαβ coupling constants and present dihedral distributions for the Φ, Ψ, as well as χ1 and χ2 angles. Finally, I present correlation plots for these dihedral angles.Key words: molecular dynamics (MD), nuclear magnetic resonance (NMR) spectroscopy, J-coupling, chemical shift, dihedral probability distribution.

A combined LX-NMR and molecular dynamics investigation of the bulk and local structure of ionic liquid crystals

Soft Matter ◽  
2019 ◽  
Vol 15 (22) ◽  
pp. 4486-4497 ◽  
Author(s):  
Maria Enrica Di Pietro ◽  
Tommaso Margola ◽  
Giorgio Celebre ◽  
Giuseppina De Luca ◽  
Giacomo Saielli
Keyword(s):  
Molecular Dynamics ◽  
Ionic Liquid ◽  
Liquid Crystals ◽  
Nmr Spectroscopy ◽  
Molecular Dynamics Simulations ◽  
Local Structure ◽  
Structural Information ◽  
Ionic Liquid Crystals ◽  
Dynamics Simulations ◽  
Unique Power

The unique power of NMR spectroscopy in anisotropic media (LX-NMR) as a tool to obtain local and bulk structural information, combined with the effectiveness of molecular dynamics simulations at the atomistic level, shows very attractive potentialities for the study of Ionic Liquid Crystals.

scholarly journals Antibody humanization—the Influence of the antibody framework on the CDR-H3 loop ensemble in solution

2019 ◽  
Vol 32 (9) ◽  
pp. 411-422 ◽  
Author(s):  
Monica L Fernández-Quintero ◽  
Martin C Heiss ◽  
Klaus R Liedl
Keyword(s):  
Structural Information ◽  
Point Mutations ◽  
Antibody Engineering ◽  
Enhanced Sampling ◽  
Loop Dynamics ◽  
Shallow Side ◽  
Dynamics Simulations ◽  
Loop Conformation ◽  
Idiotypic Antibody ◽  
Complementarity Determining Region

Abstract Antibody engineering of non-human antibodies has focused on reducing immunogenicity by humanization, being a major limitation in developing monoclonal antibodies. We analyzed four series of antibody binding fragments (Fabs) and a variable fragment (Fv) with structural information in different stages of humanization to investigate the influence of the framework, point mutations and specificity on the complementarity determining region (CDR)-H3 loop dynamics. We also studied a Fv without structural information of the anti-idiotypic antibody Ab2/3H6, because it completely lost its binding affinity upon superhumanization, as an example of a failed humanization. Enhanced sampling techniques in combination with molecular dynamics simulations allow to access micro- to milli-second timescales of the CDR-H3 loop dynamics and reveal kinetic and thermodynamic changes involved in the process of humanization. In most cases, we observe a reduced conformational diversity of the CDR-H3 loop when grafted on a human framework and find a conformational shift of the dominant CDR-H3 loop conformation in solution. A shallow side minimum of the conformational CDR-H3 loop ensemble attached to the murine framework becomes the dominant conformation in solution influenced by the human framework. Additionally, we observe in the case of the failed humanization that the potentially binding competent murine CDR-H3 loop ensemble in solution shows nearly no kinetical or structural overlap with the superhumanized variant, thus explaining the loss of binding.

Characterization of the dynamic events of GPCRs by automated computational simulations

2013 ◽  
Vol 41 (1) ◽  
pp. 205-212 ◽  
Author(s):  
Hugo Gutiérrez-de-Terán ◽  
Xabier Bello ◽  
David Rodríguez
Keyword(s):  
Structural Information ◽  
Md Simulations ◽  
Dynamic Features ◽  
Computational Simulations ◽  
A2a Adenosine Receptor ◽  
Dynamic Events ◽  
Cxc Chemokine Receptor 4 ◽  
Dynamics Simulations ◽  
Chemokine Receptor 4 ◽  
G Protein Coupled

The recent advances in membrane protein crystallography have provided extremely valuable structural information of the superfamily of GPCRs (G-protein-coupled receptors). This has been particularly true for a few receptors whose structure was solved several times under different biochemical conditions. It follows that the mechanisms of receptor conformational equilibrium and related dynamic events can be explored by computational simulations. In the present article, we summarize our recent understanding of several dynamic features of GPCRs, accomplished through the use of MD (molecular dynamics) simulations. Our pipeline for the MD simulations of GPCRs, implemented in the web service http://gpcr.usc.es, is updated in the present paper and illustrated by recent applications. Special emphasis is put on the A2A adenosine receptor, one of the selected cases where crystal structures in several conformations and conditions exist, and on the dimerization process of the CXCR4 (CXC chemokine receptor 4).

scholarly journals Accelerating Dissociative Events in Molecular Dynamics Simulations by Selective Potential Scaling

2019 ◽  
Author(s):  
Indrajit Deb ◽  
Aaron T. Frank
Keyword(s):  
Molecular Dynamics ◽  
Sampling Method ◽  
Potential Energy Function ◽  
Md Simulations ◽  
Cyclin Dependent Kinase ◽  
Enhanced Sampling ◽  
Free Energies ◽  
Biologically Relevant ◽  
Dynamics Simulations ◽  
Dissociative Processes

ABSTRACTMolecular dynamics (or MD) simulations can be a powerful tool for modeling complex dissociative processes such as ligand unbinding. However, many biologically relevant dissociative processes occur on timescales that far exceed the timescales of typical MD simulations. Here, we implement and apply an enhanced sampling method in which specific energy terms in the potential energy function are selectively “scaled” to accelerate dissociative events during simulations. Using ligand unbinding as an example of a complex dissociative process, we selectively scaled-up ligand-water interactions in an attempt to increase the rate of ligand unbinding. By applying our selectively scaled MD (or ssMD) approach to three cyclin-dependent kinase 2 (CDK2)-inhibitor complexes, we were able to significantly accelerate ligand unbinding thereby allowing, in some cases, unbinding events to occur within as little as 2 ns. Moreover, we found that we could make realistic estimates of the unbinding as well as the binding free energies (∆Gsim) of the three inhibitors from our ssMD simulation data. To accomplish this, we employed a previously described Kramers’-based rate extrapolation (KRE) method and a newly described free energy extrapolation (FEE) method. Because our ssMD approach is general, it should find utility as an easy-to-deploy, enhanced sampling method for modeling other dissociative processes.

Use of Molecular Dynamics Simulations in Structure-Based Drug Discovery

2019 ◽  
Vol 25 (31) ◽  
pp. 3339-3349 ◽  
Author(s):  
Indrani Bera ◽  
Pavan V. Payghan
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Molecular Dynamics Simulations ◽  
Drug Target ◽  
Structural Information ◽  
Drug Binding ◽  
Structure Based Drug Design ◽  
Drug Designing ◽  
Target Binding ◽  
Dynamics Simulations

Background: Traditional drug discovery is a lengthy process which involves a huge amount of resources. Modern-day drug discovers various multidisciplinary approaches amongst which, computational ligand and structure-based drug designing methods contribute significantly. Structure-based drug designing techniques require the knowledge of structural information of drug target and drug-target complexes. Proper understanding of drug-target binding requires the flexibility of both ligand and receptor to be incorporated. Molecular docking refers to the static picture of the drug-target complex(es). Molecular dynamics, on the other hand, introduces flexibility to understand the drug binding process. Objective: The aim of the present study is to provide a systematic review on the usage of molecular dynamics simulations to aid the process of structure-based drug design. Method: This review discussed findings from various research articles and review papers on the use of molecular dynamics in drug discovery. All efforts highlight the practical grounds for which molecular dynamics simulations are used in drug designing program. In summary, various aspects of the use of molecular dynamics simulations that underline the basis of studying drug-target complexes were thoroughly explained. Results: This review is the result of reviewing more than a hundred papers. It summarizes various problems that use molecular dynamics simulations. Conclusion: The findings of this review highlight how molecular dynamics simulations have been successfully implemented to study the structure-function details of specific drug-target complexes. It also identifies the key areas such as stability of drug-target complexes, ligand binding kinetics and identification of allosteric sites which have been elucidated using molecular dynamics simulations.

Sign in / Sign up

Export Citation Format

Share Document