Diffusion of atomic oxygen relevant to water formation in amorphous interstellar ices

2014 ◽  
Vol 168 ◽  
pp. 205-222 ◽  
Author(s):  
Myung Won Lee ◽  
Markus Meuwly
Keyword(s):  
Electrostatic Interactions ◽  
Atomic Oxygen ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Chemical Mechanism ◽  
Amorphous Ice ◽  
Migration Barriers ◽  
Water Formation ◽  
Interstellar Ices ◽  
Migration Pathways

Molecular dynamics (MD) simulations together with accurate physics-based force fields are employed to determine the mobility of atomic oxygen in amorphous ice at low temperatures, characteristic for conditions in interstellar ices. From the simulations it is found that the mobility of atomic oxygen ranges from 60 to 480 Å2 ns−1 in amorphous ice at temperatures between 50 and 200 K. Hence, the simulations establish that atomic oxygen is mobile to a certain degree and a chemical mechanism for water formation involving oxygen mobility is a realistic scenario. This is also confirmed by the computed migration barriers for oxygen diffusion by multiple umbrella sampling simulations, which yield barriers for diffusion in the range of 0.7–1.9 kcal mol−1. The physics-based force field – based on a multipolar expansion of the electrostatic interactions – yields more pronounced energetics for oxygen migration pathways compared to the conventional point-charge models employed in typical simulations. Once formed, the computed solvation free energy suggests that atomic oxygen thermodynamically prefers to be localized inside amorphous ice and is available for chemical reaction, which may be relevant to water formation in and on grains.

scholarly journals Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yogeeshwar Ajjugal ◽  
Kripi Tomar ◽  
D. Krishna Rao ◽  
Thenmalarchelvi Rathinavelan
Keyword(s):  
Mismatch Repair ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Base Flipping ◽  
Base Pairs ◽  
2D Noesy ◽  
Junction Formation ◽  
Nmr Techniques ◽  
Transient Events

AbstractBase pair mismatches in DNA can erroneously be incorporated during replication, recombination, etc. Here, the influence of A…A mismatch in the context of 5′CAA·5′TAG sequence is explored using molecular dynamics (MD) simulation, umbrella sampling MD, circular dichroism (CD), microscale thermophoresis (MST) and NMR techniques. MD simulations reveal that the A…A mismatch experiences several transient events such as base flipping, base extrusion, etc. facilitating B–Z junction formation. A…A mismatch may assume such conformational transitions to circumvent the effect of nonisostericity with the flanking canonical base pairs so as to get accommodated in the DNA. CD and 1D proton NMR experiments further reveal that the extent of B–Z junction increases when the number of A…A mismatch in d(CAA)·d(T(A/T)G) increases (1–5). CD titration studies of d(CAA)·d(TAG)n=5 with the hZαADAR1 show the passive binding between the two, wherein, the binding of protein commences with B–Z junction recognition. Umbrella sampling simulation indicates that the mismatch samples anti…+ syn/+ syn…anti, anti…anti & + syn…+ syn glycosyl conformations. The concomitant spontaneous transitions are: a variety of hydrogen bonding patterns, stacking and minor or major groove extrahelical movements (with and without the engagement of hydrogen bonds) involving the mismatch adenines. These transitions frequently happen in anti…anti conformational region compared with the other three regions as revealed from the lifetime of these states. Further, 2D-NOESY experiments indicate that the number of cross-peaks diminishes with the increasing number of A…A mismatches implicating its dynamic nature. The spontaneous extrahelical movement seen in A…A mismatch may be a key pre-trapping event in the mismatch repair due to the accessibility of the base(s) to the sophisticated mismatch repair machinery.

Structural insights into the repair mechanism of AGT for methyl-induced DNA damage

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Rajendra P. Koirala ◽  
Rudramani Pokhrel ◽  
Prabin Baral ◽  
Purushottam B. Tiwari ◽  
Prem P. Chapagain ◽  
...  
Keyword(s):  
Covalent Bond ◽  
Cancer Therapeutics ◽  
Md Simulations ◽  
Structural Features ◽  
Umbrella Sampling ◽  
Repair Mechanism ◽  
Structural Investigations ◽  
Methylated Dna ◽  
Dna Base ◽  
Dna Alkyltransferase

Abstract Methylation induced DNA base-pairing damage is one of the major causes of cancer. O6-alkylguanine-DNA alkyltransferase (AGT) is considered a demethylation agent of the methylated DNA. Structural investigations with thermodynamic properties of the AGT-DNA complex are still lacking. In this report, we modeled two catalytic states of AGT-DNA interactions and an AGT-DNA covalent complex and explored structural features using molecular dynamics (MD) simulations. We utilized the umbrella sampling method to investigate the changes in the free energy of the interactions in two different AGT-DNA catalytic states, one with methylated GUA in DNA and the other with methylated CYS145 in AGT. These non-covalent complexes represent the pre- and post-repair complexes. Therefore, our study encompasses the process of recognition, complex formation, and separation of the AGT and the damaged (methylated) DNA base. We believe that the use of parameters for the amino acid and nucleotide modifications and for the protein-DNA covalent bond will allow investigations of the DNA repair mechanism as well as the exploration of cancer therapeutics targeting the AGT-DNA complexes at various functional states as well as explorations via stabilization of the complex.

scholarly journals Insight into Inhibitor Binding in the Eukaryotic Proteasome: Computations of the 20S CP

2018 ◽  
Vol 19 (12) ◽  
pp. 3858
Author(s):  
Milan Hodošček ◽  
Nadia Elghobashi-Meinhardt
Keyword(s):  
Electrostatic Interactions ◽  
Active Sites ◽  
Sampling Period ◽  
Md Simulations ◽  
Structural Features ◽  
Relaxation Dynamics ◽  
Inhibitor Binding ◽  
Computational Analyses ◽  
Insight Into ◽  
Proteolytic Chamber

A combination of molecular dynamics (MD) simulations and computational analyses uncovers structural features that may influence substrate passage and exposure to the active sites within the proteolytic chamber of the 20S proteasome core particle (CP). MD simulations of the CP reveal relaxation dynamics in which the CP slowly contracts over the 54 ns sampling period. MD simulations of the SyringolinA (SylA) inhibitor within the proteolytic B 1 ring chamber of the CP indicate that favorable van der Waals and electrostatic interactions account for the predominant association of the inhibitor with the walls of the proteolytic chamber. The time scale required for the inhibitor to travel from the center of the proteolytic chamber to the chamber wall is on the order of 4 ns, accompanied by an average energetic stabilization of approximately −20 kcal/mol.

scholarly journals Molecular simulations of lipid membrane partitioning and translocation by bacterial quorum sensing modulators

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246187
Author(s):  
Tianyi Jin ◽  
Samarthaben J. Patel ◽  
Reid C. Van Lehn
Keyword(s):  
Quorum Sensing ◽  
Lipid Bilayers ◽  
Lipid Membrane ◽  
Computational Cost ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Communication Process ◽  
Free Energies ◽  
Membrane Partitioning ◽  
Solvent Model

Quorum sensing (QS) is a bacterial communication process mediated by both native and non-native small-molecule quorum sensing modulators (QSMs), many of which have been synthesized to disrupt QS pathways. While structure-activity relationships have been developed to relate QSM structure to the activation or inhibition of QS receptors, less is known about the transport mechanisms that enable QSMs to cross the lipid membrane and access intracellular receptors. In this study, we used atomistic MD simulations and an implicit solvent model, called COSMOmic, to analyze the partitioning and translocation of QSMs across lipid bilayers. We performed umbrella sampling at atomistic resolution to calculate partitioning and translocation free energies for a set of naturally occurring QSMs, then used COSMOmic to screen the water-membrane partition and translocation free energies for 50 native and non-native QSMs that target LasR, one of the LuxR family of quorum-sensing receptors. This screening procedure revealed the influence of systematic changes to head and tail group structures on membrane partitioning and translocation free energies at a significantly reduced computational cost compared to atomistic MD simulations. Comparisons with previously determined QSM activities suggest that QSMs that are least likely to partition into the bilayer are also less active. This work thus demonstrates the ability of the computational protocol to interrogate QSM-bilayer interactions which may help guide the design of new QSMs with engineered membrane interactions.

scholarly journals Identification of rare Lewis oligosaccharide conformers in aqueous solution using enhanced sampling molecular dynamics

2017 ◽  
Author(s):  
Irfan Alibay ◽  
Kepa K. Burusco ◽  
Neil J. Bruce ◽  
Richard A. Bryce
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Biological Action ◽  
Sialyl Lewis X ◽  
Enhanced Sampling ◽  
Sialyl Lewis ◽  
Aqueous Solvent ◽  
A Minor

<p>Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 ms trajectories; these simulations find a predominance of closed conformer and a range of low occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the <sup>4</sup>C<sub>1</sub> form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution, corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 ms unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.</p>

scholarly journals Defect structure in δ-Bi5PbY2O11.5

RSC Advances ◽  
2019 ◽  
Vol 9 (17) ◽  
pp. 9640-9653 ◽  
Author(s):  
Anna Borowska-Centkowska ◽  
Xi Liu ◽  
Marcin Krynski ◽  
Marzena Leszczynska ◽  
Wojciech Wrobel ◽  
...  
Keyword(s):  
Neutron Scattering ◽  
Ab Initio ◽  
Defect Structure ◽  
Md Simulations ◽  
Total Neutron ◽  
Vacancy Ordering ◽  
And Migration ◽  
Migration Pathways ◽  
Oxide Ion

Total neutron scattering analysis and ab initio MD simulations reveal details of oxide ion vacancy ordering and migration pathways.

scholarly journals Insights into the Polyhexamethylene Biguanide (PHMB) Mechanism of Action on Bacterial Membrane and DNA: A Molecular Dynamics Study

2020 ◽  
Author(s):  
Shahin Sowlati-Hashjin ◽  
Paola Carbone ◽  
Mikko Karttunen
Keyword(s):  
Molecular Dynamics ◽  
Electrostatic Interactions ◽  
Membrane Surface ◽  
Md Simulations ◽  
Phospholipid Bilayer ◽  
Phospholipid Membrane ◽  
Replication Process ◽  
Polyhexamethylene Biguanide ◽  
Phosphate Backbone ◽  
Pass Through

AbstractPolyhexamethylene biguanide (PHMB) is a cationic polymer with antimicrobial and antiviral properties. It has been commonly accepted that the antimicrobial activity is due the ability of PHMB to perforate the bacterial phospholipid membrane leading ultimately to its death. In this study we show by the means of atomistic molecular dynamics (MD) simulations that while the PHMB molecules attach to the surface of the phospholipid bilayer and partially penetrate it, they do not cause any pore formation at least within the microsecond simulation times. The polymers initially adsorb onto the membrane surface via the favourable electrostatic interactions between the phospholipid headgroups and the biguanide groups, and then partially penetrate the membrane slightly disrupting its structure. This, however, does not lead to the formation of any pores. The microsecond-scale simulations reveal that it is unlikely for PHMB to spontaneously pass through the phospholipid membrane. Our findings suggest that PHMB translocation across the bilayer may take place through binding to the phospholipids. Once inside the cell, the polymer can effectively ‘bind’ to DNA through extensive interactions with DNA phosphate backbone, which can potentially block the DNA replication process or activate DNA repair pathways.TOC Graphic

scholarly journals Rationalizing generation of broad spectrum antibiotics with the addition of a primary amine

2021 ◽  
Author(s):  
Nandan Haloi ◽  
Archit Kumar Vasan ◽  
Emily Jane Geddes ◽  
Arjun Prasanna ◽  
Po-Chao Wen ◽  
...  
Keyword(s):  
Free Energy ◽  
Primary Amine ◽  
Electrostatic Interactions ◽  
Degrees Of Freedom ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Gram Negative ◽  
Molecular Conformations ◽  
Energy Calculations ◽  
Cell Accumulation

Antibiotic resistance of Gram-negative bacteria is largely attributed to the low permeability of their outer membrane (OM). Recently, we disclosed the eNTRy rules, a key lesson of which is that the introduction of a primary amine enhances OM permeation in certain contexts. To understand the molecular basis for this finding, we perform an extensive set of molecular dynamics (MD) simulations and free energy calculations comparing the permeation of aminated and amine-free antibiotic derivatives through the most abundant OM porin of E. coli, OmpF. To improve sampling of conformationally flexible drugs in MD simulations, we developed a novel, Monte Carlo and graph theory based algorithm to probe more efficiently the rotational and translational degrees of freedom visited during the permeation of the antibiotic molecule through OmpF. The resulting pathways were then used for free-energy calculations, revealing a lower barrier against the permeation of the aminated compound, substantiating its greater OM permeability. Further analysis revealed that the amine facilitates permeation by enabling the antibiotic to align its dipole to the luminal electric field of the porin and while forming favorable electrostatic interactions with specific, highly-conserved charged residues. The importance of these interactions in permeation was further validated with experimental mutagenesis and whole cell accumulation assays. Overall, this study provides insights on the importance of the primary amine for antibiotic permeation into Gram-negative pathogens that could help the design of future antibiotics. We also offer a new computational approach for calculating free-energy of processes where relevant molecular conformations cannot be efficiently captured.

scholarly journals Electrostatic Interactions with Choline and Phosphate Groups Regulate Cisplatin Permeation through a Dioleoylphosphocholine Bilayer

2020 ◽  
Author(s):  
Lorena Ruano ◽  
Gustavo Cárdenas ◽  
Juan Jose Nogueira
Keyword(s):  
Free Energy ◽  
Lipid Bilayers ◽  
Long Range ◽  
Electrostatic Interactions ◽  
Umbrella Sampling ◽  
Energy Minimum ◽  
Free Energy Minimum ◽  
Dynamics Simulations ◽  
First Moment ◽  
Phosphate Groups

The investigation of the intermolecular interactions between platinum-based anticancer drugs and lipid bilayers is of special relevance to unveil the mechanisms involved in different steps of the mode of action of these drugs. We have simulated the permeation of cisplatin through a model membrane composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids by means of umbrella sampling classical molecular dynamics simulations. The initial physisorption of cisplatin in the polar region of the membrane is controlled, in a first moment, by long-range electrostatic interactions with the choline groups, which trap the drug in a shallow free-energy minimum. Then, cisplatin is driven to a deeper free-energy minimum by long-range electrostatic interactions with the phosphate groups. From this minimum to the middle of the bilayer the electrostatic repulsion between cisplatin and the choline groups partially cancels out the electrostatic attraction between cisplatin and the phosphate groups, inducing a general drop of the total interaction with the polar heads. In addition, the attractive interactions with the non-polar tails, which are dominated by van der Waals contributions, gain significance. The large energy barrier found when going from the global minimum to the middle of the membrane indicates that the non-electrostatic interactions between the drug and the non-polar tails are badly reproduced by the fixed point-charge force field used here, and that the introduction of polarization effects are likely necessary.

scholarly journals Sequence specificity despite intrinsic disorder: how a disease-associated Val/Met polymorphism rearranges tertiary interactions in a long disordered protein

2019 ◽  
Author(s):  
Ruchi Lohia ◽  
Reza Salari ◽  
Grace Brannigan
Keyword(s):  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Protein A ◽  
Md Simulations ◽  
Disordered Proteins ◽  
Sequence Specificity ◽  
Intrinsically Disordered ◽  
Specific Effects ◽  
Non Local

<p>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) in precursor brain-derived neurotrophic factor (BDNF) is one of the earliest SNPs to be associated with neuropsychiatric disorders, and the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica exchange molecular dynamics (MD) simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence. The simulations were able to correctly reproduce the location of both local and non-local secondary changes due to the Val66Met mutation when compared with NMR spectroscopy. We find that the change in local structure is mediated via entropic and sequence specific effects. We developed a hierarchical sequence-based framework for analysis and conceptualization, which first identifies “blobs” of 5-15 residues representing local globular regions or linkers. We use this framework within a novel test for enrichment of higher-order (tertiary) structure in disordered proteins; the size and shape of each blob is extracted from MD simulation of the real protein (RP), and used to parameterize a self-avoiding heterogenous polymer (SAHP). The SAHP version of the BDNF prodomain suggested a protein segmented into three regions, with a central long, highly disordered polyampholyte linker separating two globular regions. This effective segmentation was also observed in full simulations of the RP, but the Val66Met substitution significantly increased interactions across the linker, as well as the number of participating residues. The Val66Met substitution replaces β-bridging between Val66 and Val94 (on either side of the linker) with specific side-chain interactions between Met66 and Met95.The protein backbone in the vicinity of Met95 is then free to form β-bridges with residues 31-41 near the N-terminus, which condenses the protein. A significant role for Met/Met interactions is consistent with previously-observed non-local effects of the Val66Met SNP, as well as established interactions between the Met66 sequence and a Met-rich receptor that initiates neuronal growth cone retraction.</p>

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