Heterogeneous Interactions Promote Crystallization and Spontaneous Resolution of Chiral Molecules

2019 ◽  
Author(s):  
John Carpenter ◽  
Michael Gruenwald
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Crystallization Behavior ◽  
Amorphous Solids ◽  
Spontaneous Resolution ◽  
Low Energy ◽  
Coarse Grained ◽  
Chiral Molecules ◽  
Racemic Mixtures ◽  
Heterogeneous Interactions

Predicting the crystallization behavior of solutions of chiral molecules is a major challenge in the chemical sciences. In this paper, we use molecular dynamics computer simulations to study the crystallization of a family of coarse-grained models of chiral molecules with a broad range of molecular shapes and interactions. Our simulations reproduce the experimental crystallization behavior of real chiral molecules, including racemic and enantiopure crystals, as well as amorphous solids. Using efficient algorithms for the packing of shapes, we enumerate millions of low energy crystal structures for each model and analyze the thermodynamic landscape of polymorphs. In agreement with recent conjectures, our analysis shows that the ease of crystallization is largely determined by the number of competing polymorphs with low free energy. We find that this number, and hence crystallization outcomes, depend on molecular interactions in a simple way: Strongly heterogeneous interactions across molecules promote crystallization and favor the spontaneous resolution of racemic mixtures.

Heterogeneous Interactions Promote Crystallization and Spontaneous Resolution of Chiral Molecules

2019 ◽  
Author(s):  
John Carpenter ◽  
Michael Gruenwald
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Crystallization Behavior ◽  
Amorphous Solids ◽  
Spontaneous Resolution ◽  
Low Energy ◽  
Coarse Grained ◽  
Chiral Molecules ◽  
Racemic Mixtures ◽  
Heterogeneous Interactions

Predicting the crystallization behavior of solutions of chiral molecules is a major challenge in the chemical sciences. In this paper, we use molecular dynamics computer simulations to study the crystallization of a family of coarse-grained models of chiral molecules with a broad range of molecular shapes and interactions. Our simulations reproduce the experimental crystallization behavior of real chiral molecules, including racemic and enantiopure crystals, as well as amorphous solids. Using efficient algorithms for the packing of shapes, we enumerate millions of low energy crystal structures for each model and analyze the thermodynamic landscape of polymorphs. In agreement with recent conjectures, our analysis shows that the ease of crystallization is largely determined by the number of competing polymorphs with low free energy. We find that this number, and hence crystallization outcomes, depend on molecular interactions in a simple way: Strongly heterogeneous interactions across molecules promote crystallization and favor the spontaneous resolution of racemic mixtures.

Effective interaction between small unilamellar vesicles as probed by coarse-grained molecular dynamics simulations

2014 ◽  
Vol 86 (2) ◽  
pp. 215-222 ◽  
Author(s):  
Wataru Shinoda ◽  
Michael L. Klein
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Effective Interaction ◽  
Md Simulations ◽  
Coarse Grained ◽  
Repulsive Interaction ◽  
Spontaneous Curvature ◽  
Unilamellar Vesicles ◽  
Small Unilamellar Vesicles ◽  
Dynamics Simulations

Abstract A series of molecular dynamics (MD) simulations has been undertaken to investigate the effective interaction between vesicles including PC (phosphatidylcholine) and PE (phosphatidylethanolamine) lipids using the Shinoda–DeVane–Klein coarse-grained force field. No signatures of fusion were detected during MD simulations employing two apposed unilamellar vesicles, each composed of 1512 lipid molecules. Association free energy of the two stable vesicles depends on the lipid composition. The two PC vesicles exhibit a purely repulsive interaction with each other, whereas two PE vesicles show a free energy gain at the contact. A mixed PC/PE (1:1) vesicle shows a higher flexibility having a lower energy barrier on the deformation, which is caused by lipid sorting within each leaflet of the membranes. With a preformed channel or stalk between proximal membranes, PE molecules contribute to stabilize the stalk. The results suggest that the lipid components forming the membrane with a negative spontaneous curvature contribute to stabilize the stalk between two vesicles in contact.

scholarly journals Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation

2021 ◽  
Vol 8 ◽  
Author(s):  
Yuan-Wei Ma ◽  
Tong-You Lin ◽  
Min-Yeh Tsai
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Surface Heterogeneity ◽  
Dynamics Simulation ◽  
Coarse Grained ◽  
Fibrillar Structure ◽  
Energy Calculation ◽  
Surface Binding ◽  
Secondary Nucleation

Amyloid peptides are known to self-assemble into larger aggregates that are linked to the pathogenesis of many neurodegenerative disorders. In contrast to primary nucleation, recent experimental and theoretical studies have shown that many toxic oligomeric species are generated through secondary processes on a pre-existing fibrillar surface. Nucleation, for example, can also occur along the surface of a pre-existing fibril—secondary nucleation—as opposed to the primary one. However, explicit pathways are still not clear. In this study, we use molecular dynamics simulation to explore the free energy landscape of a free Abeta monomer binding to an existing fibrillar surface. We specifically look into several potential Abeta structural precursors that might precede some secondary events, including elongation and secondary nucleation. We find that the overall process of surface-dependent events can be described at least by the following three stages: 1. Free diffusion 2. Downhill guiding 3. Dock and lock. And we show that the outcome of adding a new monomer onto a pre-existing fibril is pathway-dependent, which leads to different secondary processes. To understand structural details, we have identified several monomeric amyloid precursors over the fibrillar surfaces and characterize their heterogeneity using a probability contact map analysis. Using the frustration analysis (a bioinformatics tool), we show that surface heterogeneity correlates with the energy frustration of specific local residues that form binding sites on the fibrillar structure. We further investigate the helical twisting of protofilaments of different sizes and observe a length dependence on the filament twisting. This work presents a comprehensive survey over the properties of fibril growth using a combination of several openMM-based platforms, including the GPU-enabled openAWSEM package for coarse-grained modeling, MDTraj for trajectory analysis, and pyEMMA for free energy calculation. This combined approach makes long-timescale simulation for aggregation systems as well as all-in-one analysis feasible. We show that this protocol allows us to explore fibril stability, surface binding affinity/heterogeneity, as well as fibrillar twisting. All these properties are important for understanding the molecular mechanism of surface-catalyzed secondary processes of fibril growth.

scholarly journals Synergistic Effect of Chemical Penetration Enhancers on Lidocaine Permeability Revealed by Coarse-Grained Molecular Dynamics Simulations

Membranes ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 410
Author(s):  
Marine E. Bozdaganyan ◽  
Philipp S. Orekhov
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Synergistic Effect ◽  
Potential Of Mean Force ◽  
Penetration Enhancers ◽  
Coarse Grained ◽  
Membrane Thickness ◽  
Free Energy Barrier ◽  
Small Molecular Weight ◽  
Chemical Penetration Enhancers

The search for new formulations for transdermal drug delivery (TDD) is an important field in medicine and cosmetology. Molecules with specific physicochemical properties which can increase the permeability of active ingredients across the stratum corneum (SC) are called chemical penetration enhancers (CPEs), and it was shown that some CPEs can act synergistically. In this study, we performed coarse-grained (CG) molecular dynamics (MD) simulations of the lidocaine delivery facilitated by two CPEs—linoleic acid (LA) and ethanol—through the SC model membrane containing cholesterol, N-Stearoylsphingosine (DCPE), and behenic acid. In our simulations, we probed the effects of individual CPEs as well as their combination on various properties of the SC membrane and the lidocaine penetration across it. We demonstrated that the addition of both CPEs decreases the membrane thickness and the order parameters of the DPCE hydrocarbon chains. Moreover, LA also enhances diffusion of the SC membrane components, especially cholesterol. The estimated potential of mean force (PMF) profiles for the lidocaine translocation across SC in the presence/absence of two individual CPEs and their combination demonstrated that while ethanol lowers the free energy barrier for lidocaine to enter SC, LA decreases the depth of the free energy minima for lidocaine inside SC. These two effects supposedly result in synergistic penetration enhancement of drugs. Altogether, the present simulations provide a detailed molecular picture of CPEs’ action and their synergistic effect on the penetration of small molecular weight therapeutics that can be beneficial for the design of novel drug and cosmetics formulations.

Curvature-driven adsorption of cationic nanoparticles to phase boundaries in multicomponent lipid bilayers

Nanoscale ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 2767-2778 ◽  
Author(s):  
Jonathan K. Sheavly ◽  
Joel A. Pedersen ◽  
Reid C. Van Lehn
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Lipid Bilayers ◽  
Negative Curvature ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Phase Boundaries ◽  
Cationic Nanoparticles ◽  
Dynamics Simulations ◽  
Curvature Driven

Coarse-grained molecular dynamics simulations and free energy calculations reveal that cationic nanoparticles preferentially adsorb to regions of intrinsic negative curvature at phase boundaries in multicomponent lipid bilayers.

Sign in / Sign up

Export Citation Format

Share Document