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.

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 Exploring New Crystal Structures of Glycine via Electric Field-Induced Structural Transformations with Molecular Dynamics Simulations

Processes ◽  
2019 ◽  
Vol 7 (5) ◽  
pp. 268 ◽  
Author(s):  
Pelin Su Bulutoglu ◽  
Conor Parks ◽  
Nandkishor K. Nere ◽  
Shailendra Bordawekar ◽  
Doraiswami Ramkrishna
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Solid State ◽  
Electric Field ◽  
Physical Properties ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
Electric Fields ◽  
High Intensity ◽  
Dynamics Simulations

Being able to control polymorphism of a crystal is of great importance to many industries, including the pharmaceutical industry, since the crystal’s structure determines significant physical properties of a material. While there are many conventional methods used to control the final crystal structure that comes out of a crystallization unit, these methods fail to go beyond a few known structures that are kinetically accessible. Recent studies have shown that externally applied fields have the potential to effectively control polymorphism and to extend the set of observable polymorphs that are not accessible through conventional methods. This computational study focuses on the application of high-intensity dc electric fields (e-fields) to induce solid-state transformation of glycine crystals to obtain new polymorphs that have not been observed via experiments. Through molecular dynamics simulations of solid-state α -, β -, and γ -glycine crystals, it has been shown that the new polymorphs sustain their structures within 125 ns after the electric field has been turned off. It was also demonstrated that strength and direction of the electric field and the initial structure of the crystal are parameters that affect the resulting polymorph. Our results showed that application of high-intensity dc electric fields on solid-state crystals can be an effective crystal structure control method for the exploration of new crystal structures of known materials and to extend the range of physical properties a material can have.

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 Combined Use of Structure Analysis, Studies of Molecular Association in Solution, and Molecular Modelling to Understand the Different Propensities of Dihydroxybenzoic Acids to Form Solid Phases

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 734
Author(s):  
Aija Trimdale ◽  
Anatoly Mishnev ◽  
Agris Bērziņš
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Structure Analysis ◽  
Crystal Structure Analysis ◽  
Molecular Association ◽  
Hydroxyl Groups ◽  
Solid Phases ◽  
Solvent Molecules ◽  
Dynamics Simulations

The arrangement of hydroxyl groups in the benzene ring has a significant effect on the propensity of dihydroxybenzoic acids (diOHBAs) to form different solid phases when crystallized from solution. All six diOHBAs were categorized into distinctive groups according to the solid phases obtained when crystallized from selected solvents. A combined study using crystal structure and molecule electrostatic potential surface analysis, as well as an exploration of molecular association in solution using spectroscopic methods and molecular dynamics simulations were used to determine the possible mechanism of how the location of the phenolic hydroxyl groups affect the diversity of solid phases formed by the diOHBAs. The crystal structure analysis showed that classical carboxylic acid homodimers and ring-like hydrogen bond motifs consisting of six diOHBA molecules are prominently present in almost all analyzed crystal structures. Both experimental spectroscopic investigations and molecular dynamics simulations indicated that the extent of intramolecular bonding between carboxyl and hydroxyl groups in solution has the most significant impact on the solid phases formed by the diOHBAs. Additionally, the extent of hydrogen bonding with solvent molecules and the mean lifetime of solute–solvent associates formed by diOHBAs and 2-propanol were also investigated.

Active site gate of M32 carboxypeptidases illuminated by crystal structure and molecular dynamics simulations

2017 ◽  
Vol 1865 (11) ◽  
pp. 1406-1415 ◽  
Author(s):  
Bhaskar Sharma ◽  
Sahayog N. Jamdar ◽  
Biplab Ghosh ◽  
Pooja Yadav ◽  
Ashwani Kumar ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Active Site ◽  
Dynamics Simulations

scholarly journals Lauryl Phosphate Flotation Chemistry in Barite Flotation

Minerals ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 280
Author(s):  
Ying Lu ◽  
Weiping Liu ◽  
Xuming Wang ◽  
Huaigang Cheng ◽  
Fangqin Cheng ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Froth Flotation ◽  
Contrast Material ◽  
Water Structure ◽  
Phosphate Adsorption ◽  
Oil Well ◽  
Wide Ph Range ◽  
Interfacial Water Structure ◽  
Dynamics Simulations

Barite has numerous applications including barium mud for oil well drilling, manufacture of elemental barium, filler for paper and rubber industries, and contrast material for X-ray radiology for the digestive system. Currently, froth flotation is the main method for the beneficiation of barite using fatty acid as a typical collector. In this research, it was found that lauryl phosphate is also a promising collector for barite flotation. Results from microflotation, contact angle, and zeta potential indicate that lauryl phosphate is adsorbed on the barite surface and thus achieves superior flotation efficiency at a wide pH range. The interfacial water structure and wetting characteristics of barite surface with/without lauryl phosphate adsorption were also evaluated by molecular dynamics simulations (MDS). The results from molecular dynamics simulations and interaction energy calculations are in accord with the experimental results, which suggest that lauryl phosphate might be a potential collector for the flotation of barite.

Sign in / Sign up

Export Citation Format

Share Document