MD Studies Research Articles

University of Minnesota Medical School.

University of Minnesota Medical School.

Development and Anti-corrosion Performance of Polymeric Epoxy Resin and their Zinc Phosphate Composite on 15CDV6 Steel in 3wt% NaCl: Experimental and Computational Studies

The evaluation of the anti-corrosive performance of polymer composite reinforced with zinc phosphate (DGEBA-DAA-ZP) acts as an effective anti-corrosive coating for 15CDV6 steel in 3wt% NaCl at different exposure times ranging from 60, 120, and 180 days in a salt spray chamber. EIS study revealed that composite formulation (DGEBA-DAA-ZP) acts as strong interface coating. Results showed that magnitude of charge transfer resistance (Rct) and coating resistance (Rpore) gradually decrease on increasing the exposure time. After 1 h exposure time, DGEBA-DAA-ZP formulation exhibited Rct and Rpore values of 16.6 kΩ cm2 and 6.16 kΩ cm2, respectively. However, after 180 days exposure, the Rct and Rpore values lower to Rct and Rpore to 4.21 kΩ cm2and 2.25 kΩ cm2, respectively. MD simulation study demonstrated that DGEBA-DAA-ZP adsorbed on the Cd surface using its flat orientation.

Discovery of new small-molecule cyclin-dependent kinase 6 inhibitors through computational approaches.

Excessive cell proliferation due to cell cycle disorders is one of the hallmarks of breast cancer. Cyclin-dependent kinases (CDKs), which are involved in the transition of the cell cycle from G1 phase to S phase by combining CDKs with cyclin, are considered promising targets with broad therapeutic potential based on their critical role in cell cycle regulation. Pharmacological evidence has shown that abnormal cell cycle due to the overexpression of CDK6 is responsible for the hyperproliferation of cancer cells. Blocking CDK6 expression inhibits tumour survival and growth. Therefore, CDK6 can be regarded as a potential target for anticancer therapeutics. Thus, small molecules that can be considered CDK inhibitors have been developed into promising anticancer drugs. In this study, combined structure-based and ligand-based in silicon models were created to identify new chemical entities against CDK6 with the appropriate pharmacokinetic properties. The database used to screen drug-like compounds in this thesis was based on the best E-pharmacophore hypothesis and the best ligand-based drug hypothesis. As a result, 147 common compounds were identified by further molecular docking. Surprisingly, the in vitro evaluation results of 20 of those compounds showed that the two had good CDK6 inhibitory effects. The best compound was subjected to kinase panel screening, followed by molecular dynamic simulations. The 50-ns MD studies revealed the pivotal role of VAL101 in the binding of inhibitors to CDK6. Overall, the identification of two new chemical entities with CDK6 inhibitory activity demonstrated the feasibility and potential of the new method.

Abstract B11: Computational insights on the druggability of TEAD YAP-binding domain

Abstract Transcriptional enhanced associate domain (TEAD) proteins are the downstream effectors of the Hippo signaling pathway that regulate cell proliferation and stem cell functions. The expression of TEAD family is upregulated in many cancer types including pancreatic, colorectal, breast, and prostate cancers, which is correlated with poor survival in patients. Pharmacologic modulators of TEADs could therefore find application in cancer treatment and regenerative medicine. In this presentation, we report our exploration of the TEAD2 Yap-binding domain conformational ensemble and its binding interaction characteristics with peptides and small molecules, using both molecular dynamics simulation and experimental binding studies with FP probes. We carried a series of conventional, cosolvent, and Gaussian-biased MD studies and discovered that the binding subsites II and III possess considerable flexibility as the free energy calculations indicate that multiple low-energy states exist with only about 1.4 Kcal/mol barriers among them. Together with the binding results, our study points to additional “hot spots”/pharmacophores for fresh design of novel small-molecule inhibitors disrupting YAP/TEAD protein-protein interactions. Note: This abstract was not presented at the conference. Citation Format: Yiping Li, Wei Zhou, Chenglong Li. Computational insights on the druggability of TEAD YAP-binding domain [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B11.

High variability of food and nutrient intake exists across the Mediterranean Dietary Pattern-A systematic review.

A Mediterranean style dietary pattern (MDP) is considered beneficial for health. The MD Score (MDS) definition has evolved, resulting in considerable variability in the foods and nutrients associated with MDS adherence. We systematically investigated food and nutrient composition of the MD between studies, countries, and methods of classifying the MDS. We searched Embase for MD systematic reviews and selected observational studies reporting intakes of foods, macronutrients, or micronutrients by categories of MDS adherence. The percentage differences in food and nutrient intakes between categories of high and low adherence to the MDS were calculated for each study. A total of 369 full‐text primary papers were reviewed from the included systematic reviews and 74 papers selected (66 adults, 8 children). We found considerable differences in MDS definitions and scoring criteria. Between‐study variation in food intake between high‐ and low‐adherence MDS adherence categories ranged from a mean of −23% for meat, to 119% for fruit, and 278% for fish. Greater variability was evident in non‐Mediterranean than Mediterranean regions. We conclude that few studies report food and nutrient intakes across the range of the MDP in adults and even fewer in children. The considerable variability in the foods and nutrients reported makes comparison of results from studies and translation into dietary guidelines difficult. We recommend that future publications of MD studies include full details of the range of food and nutrient intakes across the distribution of MD adherence in order to facilitate translation into health policy and practice.

MD study of surface collision cascades in nickel

Collision cascades initiated by fast Ni projectiles with energy E = 5, 10, 15 and 20 keV at the surface of nickel target at temperature T = 100, 300, 600, 900 and 1200 K were studied by molecular dynamics simulations. Representative sampling of 24 surface collision cascades per E,T set was generated to get the statistically reliable number of Frenkel pairs NFP and the fraction of vacancies σvac and self-interstitial atoms (SIAs) σSIA in point defect clusters as functions of the projectile energy and irradiation temperature. It was established that NFP,σvac and σSIA in surface collision cascades in nickel averaged over cascade series with the same E,T are higher than those produced in collision cascades in the bulk of the material under the same simulation conditions. Point defects generated in surface cascades predominantly agglomerate into clusters. Spatial separation of vacancies and SIAs due to the interaction of collision cascades with the free surface is the major driving mechanism responsible for the increased number of NFP,σvac and σSIA produced in surface collision cascades in nickel.

Adsorption behavior of thiophene on MoS2 under a microwave electric field via DFT and MD studies

The adsorption behavior of sulfide over catalyst is the key to determine the desulfurization efficiency and its proceeding route. Molecular dynamics and density functional theory calculations were performed to provide theoretical insight into the effect of microwave electric field on the adsorption of thiophene over different MoS2 nanocrystallites, and investigate the electronic distribution. The adsorption position and configuration were significantly affected by microwave field, and the polarities of thiophene molecule and MoS2 were strengthened, which is beneficial to the cleavage of the thiophene C–S bond. Mo atoms lose charge in a large area and have a strong electrophilic effect after the generation of S vacancy, inducing S component adsorption on active sites. The hydrodesulfurization (HDS) selectivity is modified by affecting the priority of potential adsorption. Thiophene favors to η5 adsorption over multilayer dispersed MoS2 clusters under microwave field, inducing the HDS reactions to proceed along the hydrogenation route.

A T2 Translational Science Modified Delphi Study: Spinal Motion Restriction in a Resource-Scarce Environment.

Emerging evidence is guiding changes in prehospital management of potential spinal injuries. The majority of settings related to current recommendations are in resource-rich environments (RREs), whereas there is a lack of guidance on the provision of spinal motion restriction (SMR) in resource-scarce environments (RSEs), such as: mass-casualty incidents (MCIs); low-middle income countries; complex humanitarian emergencies; conflict zones; and prolonged transport times. The application of Translational Science (TS) in the Disaster Medicine (DM) context was used to develop this study, leading to statements that can be used in the creation of evidence-based clinical guidelines (CGs). What is appropriate SMR in RSEs? The first round of this modified Delphi (mD) study was a structured focus group conducted at the World Association for Disaster and Emergency Medicine (WADEM) Congress in Brisbane Australia on May 9, 2019. The result of the focus group discussion of open-ended questions produced ten statements that were added to ten statements derived from Fischer (2018) to create the second mD round questionnaire.Academic researchers and educators, operational first responders, or first receivers of patients with suspected spinal injuries were identified to be mD experts. Experts rated their agreement with each statement on a seven-point linear numeric scale. Consensus amongst experts was defined as a standard deviation ≤1.0. Statements that were in agreement reaching consensus were included in the final report; those that were not in agreement but reached consensus were removed from further consideration. Those not reaching consensus advanced to the third mD round.For subsequent rounds, experts were shown the mean response and their own response for each of the remaining statements and asked to reconsider their rating. As above, those that did not reach consensus advanced to the next round until consensus was reached for each statement. Twenty-two experts agreed to participate with 19 completing the second mD round and 16 completing the third mD round. Eleven statements reached consensus. Nine statements did not reach consensus. Experts reached consensus offering 11 statements to be incorporated into the creation of SMR CGs in RSEs. The nine statements that did not reach consensus can be further studied and potentially modified to determine if these can be considered in SMR CGs in RSEs.

Gas Sensing by Bacterial H-NOX Proteins: An MD Study.

Gas sensing is crucial for both prokaryotes and eukaryotes and is primarily performed by heme-based sensors, including H-NOX domains. These systems may provide a new, alternative mode for transporting gaseous molecules in higher organisms, but for the development of such systems, a detailed understanding of the ligand-binding properties is required. Here, we focused on ligand migration within the protein matrix: we performed molecular dynamics simulations on three bacterial (Ka, Ns and Cs) H-NOX proteins and studied the kinetics of CO, NO and O2 diffusion. We compared the response of the protein structure to the presence of ligands, diffusion rate constants, tunnel systems and storage pockets. We found that the rate constant for diffusion decreases in the O2 > NO > CO order in all proteins, and in the Ns > Ks > Cs order if single-gas is considered. Competition between gases seems to seriously influence the residential time of ligands spent in the distal pocket. The channel system is profoundly determined by the overall fold, but the sidechain pattern has a significant role in blocking certain channels by hydrophobic interactions between bulky groups, cation–π interactions or hydrogen bonding triads. The majority of storage pockets are determined by local sidechain composition, although certain functional cavities, such as the distal and proximal pockets are found in all systems. A major guideline for the design of gas transport systems is the need to chemically bind the gas molecule to the protein, possibly joining several proteins with several heme groups together.

Comparative Study of Optical Silicon Nanomachining Experimental Results and MD Simulation Outputs

The high strength and good optical performance offered by optical grade silicon could be considered as the reason for its wide usage as optical materials in many industries including electronic, metrology, infrared (IR) optics and solar cells. Due to this, nanoscale manufacturing of these products requires superior quality and enhanced functional performance of the produced materials. Because recent studies have been focusing on correlating both surface and subsurface nature alterations with better functional performance, an MD study of the experiment was carried out in comparison with experiment to match the observed MD model features to the experimental result obtained. The MD study was observed to conform with the Ra result as obtained in the experiment.

Binding modes of cabazitaxel with the different human β-tubulin isotypes: DFT and MD studies.

Taxanes (paclitaxel, docetaxel, cabazitaxel) are anticancer drugs as microtubule inhibitors. Following our previous studies on paclitaxel and docetaxel, in this work, we examine cabazitaxel and compare these three taxenes. The binding interaction of three taxanes with various β-tubulin isotypes is studied by homology modeling, molecular docking, and molecular dynamics simulations. The results show that the effects of docetaxel on βI-tubulin (- 29.5kcal/mol) and of paclitaxel on βIIa-tubulin (- 25.5kcal/mol) are much stronger than their effects on βIII-tubulin (- 17.8kcal/mol and - 8.6kcal/mol, respectively). However, the effect of cabazitaxel on βIII-tubulin (- 23.0kcal/mol) is comparable with that on βI-tubulin (- 24.0kcal/mol) and βIIa-tubulin (- 25.9kcal/mol), consistent with the fact that overexpression of βIII-tubulin increases the drug resistance to paclitaxel and docetaxel, but has little influence for cabazitaxel. This theoretical research supports the use of cabazitaxel for patients who are resistant to the action of paclitaxel and docetaxel.

Improvements needed in palliative care services.

Improvements needed in palliative care services.

MD simulation studies of the physical and mechanical properites of P3HT-based blends

In this research, the physical and mechanical properties of semi-crystalline polymerpoly-(3-hexylthiophene-2,5-diyl)-based blends were investigated. The volume versus temperature curves of polymerpoly-(3-hexylthiophene-2,5-diyl)/methano-fullerene derivative[6]-phenyl-C64-butyricacidmethyl ester (P3HT:PCBM) and polymerpoly-(3-hexylthiophene-2,5-diyl)/DOCN-PPV (P3HT/CNPh-PPV) were plotted; however, we obtained one single temperature for each curve between glass transition temperatures of the compounds, which could be considered a good indicator of miscibility. In addition, the Coesif energy density of P3HT, PCBM, and CNPh-PPV were calculated and used to obtain the solubility parameters δP3HT, δPCBM, and δCNPh-PPV. The interaction parameter χ was calculated and used in the investigation and we confirmed the miscibility of our polymer systems. By using the dissipative particle dynamic method, the morphologies of P3HT/PCBM and P3HT/CNPh-PPV were enhanced.

Role of Asp190 in the Phosphorylation of the Antibiotic Kanamycin Catalyzed by the Aminoglycoside Phosphotransferase Enzyme: A Combined QM:QM and MD Study.

The aminoglycoside phosphotransferase (APH(3')-IIIa) kinases form a clinically central group of antibiotic-resistant enzymes. Computationally, we have studied the catalytic mechanism of the APH(3')-IIIa enzyme at the atomic-level. The proposed reaction mechanism involves protonation of Asp190 by the kanamycin 3'-hydroxyl group mediated through an explicit neighboring water molecule, which leads to a simultaneous nucleophilic attack on the γ-phosphate of the ATP by the deprotonated kanamycin 3'-hydroxyl group. The second step is a proton abstraction from the protonated Asp190 to the phosphate group of the phosphorylated kanamycin mediated by an explicit water molecule. The calculated Gibbs energy of activation (ΔG⧧) of the rate-determining step for the phosphorylation reaction is 77 kJ mol-1 at the M06-2X/6-311++G(2df,p)//ONIOM(M06-2X/6-31+G(d):HF/6-31G(d)) level of theory. This study has provided a new understanding of the APH(3')-IIIa catalytic mechanism that agrees with the available experimental data (ΔG⧧ = 75 ± 4 kJ mol-1) and could provide a starting point for the rational design of mechanism-based inhibitors of aminoglycoside modifying enzyme to circumvent antibiotic resistance.

QM and QM/MM umbrella sampling MD study of the formation of Hg(II)-thymine bond: Model for evaluation of the reaction energy profiles in solutions with constant pH.

The formation of the Hg-N3(T) bond between the 1-methylthymine (T) molecule and the hydrated Hg2+ cation was explored with the combined quantum mechanics/molecular mechanics (QM/MM) method including Free Energy Perturbation corrections. The thermodynamic properties were determined in the whole pH range, when these systems were explicitly investigated and considered as the QM part: (1) T + [Hg(H2 O)6 ]2+ , (2) T + [Hg(H2 O)5 (OH)]+ , (3) T + Hg(H2 O)4 (OH)2 , and (4) N3-deprotonated T + Hg(H2 O)4 (OH)2 . The MM part contained only solvent molecules and counterions. As a result, the dependence of Gibbs-Alberty reaction free energy on pH was obtained along the reaction coordinate. We found that an endoergic reaction in acidic condition up to pH < 4-5 becomes exoergic for a higher pH corresponding to neutral and basic solutions. The migration of the Hg2+ cation between N3 and O4/2 positions in dependence on pH is discussed as well. For the verification, DFT calculations of stationary points were performed confirming the qualitative trends of QM/MM MD simulations and NMR parameters were determined for them.

Evolved Fusarium oxysporum laccase expressed in Saccharomyces cerevisiae

Fusarium oxysporum laccase was functionally expressed in Saccharomyces cerevisiae and engineered towards higher expression levels and higher reactivity towards 2,6-dimethoxyphenol, that could be used as a mediator for lignin modification. A combination of classical culture optimization and protein engineering led to around 30 times higher activity in the culture supernatant. The winner mutant exhibited three times lower Km, four times higher kcat and ten times higher catalytic efficiency than the parental enzyme. The strategy for laccase engineering was composed of a combination of random methods with a rational approach based on QM/MM MD studies of the enzyme complex with 2,6-dimethoxyphenol. Laccase mediator system with 2,6-dimethoxyphenol caused fulvic acids release from biosolubilized coal.

Chemokines and galectins form heterodimers to modulate inflammation

Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin‐1 and galectin‐3, we identified several interacting pairs, such as CXCL12 and galectin‐3. Based on NMR and MD studies of the CXCL12/galectin‐3 heterodimer, we identified contact sites between CXCL12 β‐strand 1 and Gal‐3 F‐face residues. Mutagenesis of galectin‐3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin‐3, but not its mutants, inhibited CXCL12‐induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin‐3 attenuated CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted.

Study on Ergosterol and Cholesterol Conformational Freedom and Their Different Interaction with a Popc/Sm Bilayer. An AFM and MD Study

Study on Ergosterol and Cholesterol Conformational Freedom and Their Different Interaction with a Popc/Sm Bilayer. An AFM and MD Study

Phospholipid and Temperature Dependence of TRPV1 Dynamics

The transient receptor potential vanilloid-1 (TRPV1) is a tetrameric nonselective cation channel that acts as a conduit for a variety of external stimuli, including noxious heat, acidosis, and ligand binding, whose signaling ultimately leads to pain sensation. Activation gates the channel, allowing the influx of cations, which subsequently depolarizes the neuron. As an alternative to traditional pain treatments, modulating the behavior of TRPV1 is now the focus of significant drug-discovery efforts. Recently cryo-EM structures of TRPV1 in both the closed(apo) and open states have been reported. Such structures provide an exceptional starting point for structure-based drug discovery, as well as, the unraveling of the biophysical features of temperature activation. Using the crystal structure of the intracellular ankyrin unit and these cryo-EM structures, we have recently built a full length model of the apo-human TRPV1 homo-tetramer. The cryo-EM structure of apo-TRPV1 includes density identified with phospholipid both in the vanilloid binding site and an adjacent region between the S1-S2 helices. The role of these phospholipids in the dynamics and activation of TRPV1 remains elusive. In particular PI(4,5)P2 (phosphatidylinositol 4,5 biphosphate), a known ion channel regulator localized on the inner leaflet of plasma membranes, has been implicated in modulating TRPV1. This work has identified C-terminal binding site residues. To obtain an atomic description of the behavior of the TRPV1 channel with bound phospholipid, we have initiated molecular dynamics simulations in a membrane model (POPC). Simulations include the 1) full apo-TRPV1, 2) channel with a phospholipid bound in the S1-S2 site of each monomer, and 3) inclusion of PI(4,5)P2 in the inner leaflet. These simulations are run at physiological as well as elevated temperatures. The results of these simulations will be presented and discussed with respect to experiment and earlier MD studies. [Support:NIDA-RO1-DA003934 to PHR]

Mg2+ vs Ca2+ bound active site of group II intron– A MD study

Group II introns are enzymes which undergo self-splicing and remove itself from pre-messenger RNA. X-ray structures of group II intron of Oceanobacillus iheyensis at various stages of the self-splicing pathway (pre-hydrolytic, post-hydrolytic, and ligand-free state) revealed intricate atomic interaction network in the active site of the intron. It has been confirmed that a heteronuclear metal ion cluster consisting of four metal ions (K1, K2 sites with K+ and M1, M2 sites with Mg2+) are crucial for function. Substitution of Mg2+ by Ca2+ results in loss of enzymatic activity. The X-ray structures not only opens up the possibility of modelling Mg2+ and Ca2+ bound active site of group II intron and quantitatively estimate the energetics of Mg2+ vs Ca2+ preference but also explore the relative structural and dynamical differences in response to divalent metal ion substitution. Thus, using X-ray structures as a template we performed molecular dynamics simulations to compare structural and dynamical differences between Mg2+ and Ca2+ bound active site of group II intron at various stages of the splicing pathway (i.e., pre-hydrolytic, post-hydrolytic, and ligand-free state). Quantitative estimation of Mg2+ vs Ca2+ selectivity at the M1, M2 sites confirmed Mg2+ preference at intron active sites relative to Ca2+. Ca2+ is relatively more hydrated in the intron active site relative to Mg2+. The local environment (bound nucleophilic water, interaction with scissile phosphate) around M2 is strikingly different between Mg2+ and Ca2+ bound pre-hydrolytic state. In the post-hydrolytic state, the exon part of the hydrolysis product is involved in direct interaction with the M1, whereas the intron part is highly flexible in our MD trajectories. Solvent exposure of M1, M2 sites are least in the pre-hydrolytic state, highest in the ligand-free state, and intermediate in the post-hydrolytic state.