Crown ether conformations in 1,3-calix[4]arene bis(crown ethers): crystal structures of a caesium complex and solvent adducts and molecular dynamics simulations *

1997 ◽  
pp. 4191-4202 ◽  
Author(s):  
Pierre Thuéry, ◽  
Martine Nierlich ◽  
Jeffrey C. Bryan ◽  
Véronique Lamare ◽  
Jean-François Dozol ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Crown Ether ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
Crown Ethers ◽  
Dynamics Simulations

scholarly journals 4094 Structural Determinants of Immunogenicity for Peptide-Based Immunotherapy

2020 ◽  
Vol 4 (s1) ◽  
pp. 16-16
Author(s):  
Jason Devlin ◽  
Jesus Alonso ◽  
Grant Keller ◽  
Sara Bobisse ◽  
Alexandre Harari ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
T Cell Receptor ◽  
Tumor Regression ◽  
Recombinant Expression ◽  
Cell Receptor ◽  
Protein Crystal ◽  
Dynamics Simulations

OBJECTIVES/GOALS: Neoantigen vaccine immunotherapies have shown promise in clinical trials, but identifying which peptides to include in a vaccine remains a challenge. We aim to establish that molecular structural features can help predict which neoantigens to target to achieve tumor regression. METHODS/STUDY POPULATION: Proteins were prepared by recombinant expression in E. coli followed by in vitro refolding. Correctly folded proteins were purified by chromatography. Affinities of protein-protein interactions were measured by surface plasmon resonance (SPR) and thermal stabilities of proteins were determined by differential scanning fluorimetry. All experiments were performed at least in triplicate. Protein crystals were obtained by hanging drop vapor diffusion. The protein crystal structures were solved by molecular replacement and underwent several rounds of automated refinement. Molecular dynamics simulations were performed using the AMBER molecular dynamics package. RESULTS/ANTICIPATED RESULTS: A T cell receptor (TCR) expressed by tumor-infiltrating T cells exhibited a 20-fold stronger binding affinity to the neoantigen peptide compared to the self-peptide. X-ray crystal structures of the peptides with the major histocompatibility complex (MHC) protein demonstrated that a non-mutated residue in the peptide samples different positions with the mutation. The difference in conformations of the non-mutated residue was supported by molecular dynamics simulations. Crystal structures of the TCR engaging both peptide/MHCs suggested that the conformation favored by the mutant peptide was crucial for TCR binding. The TCR bound the neoantigen/MHC with faster binding kinetics. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that the mutation impacts the conformation of another residue in the peptide, and this alteration allows for more favorable T cell receptor binding to the neoantigen. This highlights the potential of non-mutated residues in contributing to neoantigen recognition.

scholarly journals Reducing Crystal Structure Overprediction of Ibuprofen with Large Scale Molecular Dynamics Simulations

2021 ◽  
Author(s):  
Nicholas Francia ◽  
Louise Price ◽  
Matteo Salvalaglio
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
Finite Temperature ◽  
Structure Prediction ◽  
Large Scale ◽  
Lattice Energy ◽  
Racemic Mixture ◽  
Dynamics Simulations

<p>The control of the crystal form is a central issue in the pharmaceutical industry. The identification of putative polymorphs through Crystal Structure Prediction (CSP) methods is based on lattice energy calculations, which are known to significantly over-predict the number of plausible crystal structures. A valuable tool to reduce overprediction is to employ physics-based, dynamic simulations to coalesce lattice energy minima separated by small barriers into a smaller number of more stable geometries once thermal effects are introduced. Molecular dynamics simulations and enhanced sampling methods can be employed in this context to simulate crystal structures at finite temperature and pressure. </p><p>Here we demonstrate the applicability of approaches based on molecular dynamics to systematically process realistic CSP datasets containing several hundreds of crystal structures. The system investigated is ibuprofen, a conformationally flexible active pharmaceutical ingredient that crystallises both in enantiopure forms and as a racemic mixture. By introducing a hierarchical approach in the analysis of finite-temperature supercell configurations, we can post-process a dataset of 555 crystal structures, identifying 65% of the initial structures as labile, while maintaining all the experimentally known crystal structures in the final, reduced set. Moreover, the extensive nature of the initial dataset allows one to gain quantitative insight into the persistence and the propensity to transform of crystal structures containing common hydrogen-bonded intermolecular interaction motifs.</p>

scholarly journals Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations

2016 ◽  
Vol 147 (3) ◽  
pp. 553-563 ◽  
Author(s):  
Marcus Wieder ◽  
Ugo Perricone ◽  
Thomas Seidel ◽  
Stefan Boresch ◽  
Thierry Langer
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
Dynamics Simulations ◽  
Pharmacophore Models

scholarly journals Effects of Proline Substitutions on the Thermostable LOV Domain from Chloroflexus aggregans

Crystals ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 256 ◽  
Author(s):  
Alina Remeeva ◽  
Vera V. Nazarenko ◽  
Ivan M. Goncharov ◽  
Anna Yudenko ◽  
Anastasia Smolentseva ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Fluorescence Microscopy ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
Melting Temperature ◽  
General Structure ◽  
Thermal Stabilization ◽  
Lov Domain ◽  
Proline Substitution ◽  
Dynamics Simulations

Light-oxygen-voltage (LOV) domains are ubiquitous photosensory modules found in proteins from bacteria, archaea and eukaryotes. Engineered versions of LOV domains have found widespread use in fluorescence microscopy and optogenetics, with improved versions being continuously developed. Many of the engineering efforts focused on the thermal stabilization of LOV domains. Recently, we described a naturally thermostable LOV domain from Chloroflexus aggregans. Here we show that the discovered protein can be further stabilized using proline substitution. We tested the effects of three mutations, and found that the melting temperature of the A95P mutant is raised by approximately 2 °C, whereas mutations A56P and A58P are neutral. To further evaluate the effects of mutations, we crystallized the variants A56P and A95P, while the variant A58P did not crystallize. The obtained crystal structures do not reveal any alterations in the proteins other than the introduced mutations. Molecular dynamics simulations showed that mutation A58P alters the structure of the respective loop (Aβ-Bβ), but does not change the general structure of the protein. We conclude that proline substitution is a viable strategy for the stabilization of the Chloroflexus aggregans LOV domain. Since the sequences and structures of the LOV domains are overall well-conserved, the effects of the reported mutations may be transferable to other proteins belonging to this family.

scholarly journals Water structure in solution and crystal molecular dynamics simulations compared to protein crystal structures

RSC Advances ◽  
2020 ◽  
Vol 10 (14) ◽  
pp. 8435-8443
Author(s):  
Octav Caldararu ◽  
Majda Misini Ignjatović ◽  
Esko Oksanen ◽  
Ulf Ryde
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
Water Structure ◽  
Protein Crystal ◽  
Local Clustering ◽  
Dynamics Simulations ◽  
Structure In Solution

Molecular dynamics simulations can reproduce the water structure around proteins in crystal structure only if a local clustering is performed.

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