Role of Resultant Dipole Moment in Mechanical Dissociation of Biological Complexes

Protein-peptide interactions play essential roles in many cellular processes and their structural characterization is the major focus of current experimental and theoretical research. Two decades ago, it was proposed to employ the steered molecular dynamics (SMD) to assess the strength of protein-peptide interactions. The idea behind using SMD simulations is that the mechanical stability can be used as a promising and an efficient alternative to computationally highly demanding estimation of binding affinity. However, mechanical stability defined as a peak in force-extension profile depends on the choice of the pulling direction. Here we propose an uncommon choice of the pulling direction along resultant dipole moment (RDM) vector, which has not been explored in SMD simulations so far. Using explicit solvent all-atom MD simulations, we apply SMD technique to probe mechanical resistance of ligand-receptor system pulled along two different vectors. A novel pulling direction—when ligand unbinds along the RDM vector—results in stronger forces compared to commonly used ligand unbinding along center of masses vector. Our observation that RDM is one of the factors influencing the mechanical stability of protein-peptide complex can be used to improve the ranking of binding affinities by using mechanical stability as an effective scoring function.

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Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

Current Pharmaceutical Design ◽

10.2174/1381612825666190304123545 ◽

2019 ◽

Vol 25 (7) ◽

pp. 750-773 ◽

Cited By ~ 11

Author(s):

Pabitra Narayan Samanta ◽

Supratik Kar ◽

Jerzy Leszczynski

Keyword(s):

Drug Targets ◽

Biological Activities ◽

Scoring Function ◽

Md Simulations ◽

Energy Calculation ◽

Binding Modes ◽

Macromolecular Systems ◽

In Silico Modeling ◽

Mathematical Algorithms ◽

The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

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Exploring the Structure–Performance Relationship of Sulfonated Polysulfone Proton Exchange Membrane by a Combined Computational and Experimental Approach

Polymers ◽

10.3390/polym13060959 ◽

2021 ◽

Vol 13 (6) ◽

pp. 959

Author(s):

Cataldo Simari ◽

Mario Prejanò ◽

Ernestino Lufrano ◽

Emilia Sicilia ◽

Isabella Nicotera

Keyword(s):

High Performance ◽

Mechanical Stability ◽

Structural Parameters ◽

Hydration Number ◽

Pem Fuel Cells ◽

Proton Exchange ◽

Water Dynamics ◽

Mechanical Resistance ◽

Theoretical Simulation ◽

Sulfonated Polysulfone

Sulfonated Polysulfone (sPSU) is emerging as a concrete alternative to Nafion ionomer for the development of proton exchange electrolytic membranes for low cost, environmentally friendly and high-performance PEM fuel cells. This ionomer has recently gained great consideration since it can effectively combine large availability on the market, excellent film-forming ability and remarkable thermo-mechanical resistance with interesting proton conductive properties. Despite the great potential, however, the morphological architecture of hydrated sPSU is still unknown. In this study, computational and experimental advanced tools are combined to preliminary describe the relationship between the microstructure of highly sulfonated sPSU (DS = 80%) and its physico-chemical, mechanical and electrochemical features. Computer simulations allowed for describing the architecture and to estimate the structural parameters of the sPSU membrane. Molecular dynamics revealed an interconnected lamellar-like structure for hydrated sPSU, with ionic clusters of about 14–18 Å in diameter corresponding to the hydrophilic sulfonic-acid-containing phase. Water dynamics were investigated by 1H Pulsed Field Gradient (PFG) NMR spectroscopy in a wide temperature range (20–120 °C) and the self-diffusion coefficients data were analyzed by a “two-sites” model. It allows to estimate the hydration number in excellent agreement with the theoretical simulation (e.g., about 8 mol H2O/mol SO3− @ 80 °C). The PEM performance was assessed in terms of dimensional, thermo-mechanical and electrochemical properties by swelling tests, DMA and EIS, respectively. The peculiar microstructure of sPSU provides a wider thermo-mechanical stability in comparison to Nafion, but lower dimensional and conductive features. Nonetheless, the single H2/O2 fuel cell assembled with sPSU exhibited better features than any earlier published hydrocarbon ionomers, thus opening interesting perspectives toward the design and preparation of high-performing sPSU-based PEMs.

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Atomistic Analysis of ToxN and ToxI Complex Unbinding Mechanism

International Journal of Molecular Sciences ◽

10.3390/ijms19113524 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3524 ◽

Cited By ~ 6

Author(s):

Guodong Hu ◽

Xiu Yu ◽

Yunqiang Bian ◽

Zanxia Cao ◽

Shicai Xu ◽

...

Keyword(s):

Molecular Dynamics ◽

Noncoding Rna ◽

Md Simulations ◽

Normal Function ◽

Toxin Complex ◽

Potentials Of Mean Force ◽

Protein Toxins ◽

Function Relationship ◽

The Stability ◽

Smd Simulations

ToxIN is a triangular structure formed by three protein toxins (ToxNs) and three specific noncoding RNA antitoxins (ToxIs). To respond to stimuli, ToxI is preferentially degraded, releasing the ToxN. Thus, the dynamic character is essential in the normal function interactions between ToxN and ToxI. Here, equilibrated molecular dynamics (MD) simulations were performed to study the stability of ToxN and ToxI. The results indicate that ToxI adjusts the conformation of 3′ and 5′ termini to bind to ToxN. Steered molecular dynamics (SMD) simulations combined with the recently developed thermodynamic integration in 3nD (TI3nD) method were carried out to investigate ToxN unbinding from the ToxIN complex. The potentials of mean force (PMFs) and atomistic pictures suggest the unbinding mechanism as follows: (1) dissociation of the 5′ terminus from ToxN, (2) missing the interactions involved in the 3′ terminus of ToxI without three nucleotides (G31, A32, and A33), (3) starting to unfold for ToxI, (4) leaving the binding package of ToxN for three nucleotides of ToxI, (5) unfolding of ToxI. This work provides information on the structure-function relationship at the atomistic level, which is helpful for designing new potent antibacterial drugs in the future.

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Nanomechanics combined with HDX reveal allosteric drug binding sites of CFTR NBD1

10.1101/2021.08.20.457065 ◽

2021 ◽

Author(s):

Rita Padanyi ◽

Bianka Farkas ◽

Hedvig Tordai ◽

Balint Kiss ◽

Helmut Grubmuller ◽

...

Keyword(s):

Binding Sites ◽

Thermal Stabilization ◽

Drug Efficacy ◽

Md Simulations ◽

Drug Binding ◽

Structural Defects ◽

Mechanical Resistance ◽

Atomic Force ◽

Δf508 Cftr ◽

Hydrogen Deuterium

Cystic fibrosis is most frequently caused by the deletion of F508 (ΔF508) in CFTR's nucleotide binding domain 1 (NBD1), thereby compromising CFTR folding, stability and domain assembly. Limitation to develop a successful therapy has been attributed to the lack of molecules that synergistically facilitate folding by targeting distinct structural defects of ΔF508-CFTR. To improve drug efficacy by targeting the ΔF508-NBD1 folding and stability, and to study potential ΔF508-NBD1 allosteric corrector binding sites at the atomic level, we combined molecular dynamics (MD) simulations, atomic force spectroscopy (AFM) and hydrogen-deuterium exchange (HDX) experiments to elucidate the mechanical and thermal stabilization mechanisms of ΔF508-NBD1 by 5-bromoindole-3-acetic acid (BIA). MD and AFM allowed us to describe unfolding intermediates and forces acting during NBD1 mechanical unfolding. Application of the low-potency corrector BIA increased the mechanical resistance of the ΔF508-NBD1 α-subdomain, which was confirmed as a binding site by computational modeling and HDX experiments. Our results underline the complementarity of MD and AFM despite their different pulling speeds and provide a possible strategy to improve folding correctors.

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Interactive Mechanism of Potential Inhibitors with Glycosyl for SARS-CoV-2 by Molecular Dynamics Simulation

Processes ◽

10.3390/pr9101749 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1749

Author(s):

Yuqi Zhang ◽

Li Chen ◽

Xiaoyu Wang ◽

Yanyan Zhu ◽

Yongsheng Liu ◽

...

Keyword(s):

Molecular Dynamics ◽

Small Molecules ◽

Binding Sites ◽

Md Simulations ◽

Experimental Methods ◽

Dynamics Simulation ◽

Theoretical Research ◽

Stacking Interactions ◽

Receptor Binding Domain ◽

Potential Inhibitors

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a type of Ribonucleic Acid (RNA) coronavirus and it has infected and killed many people around the world. It is reported that the receptor binding domain of the spike protein (S_RBD) of the SARS-CoV-2 virus is responsible for attachment to human angiotensin converting enzyme II (ACE2). Many researchers are attempting to search potential inhibitors for fighting SARS-CoV-2 infection using theoretical or experimental methods. In terms of experimental and theoretical research, Cefuroxime, Erythromycin, Lincomycin and Ofloxacin are the potential inhibitors of SARS-CoV-2. However, the interactive mechanism of the protein SARS-CoV-2 and the inhibitors are still elusive. Here, we investigated the interactions between S_RBD and the inhibitors using molecular dynamics (MD) simulations. Interestingly, we found that there are two binding sites of S_RBD for the four small molecules. In addition, our analysis also illustrated that hydrophobic and π-π stacking interactions play crucial roles in the interactions between S_RBD and the small molecules. In our work, we also found that small molecules with glycosyl group have more effect on the conformation of S_RBD than other inhibitors, and they are also potential inhibitors for the genetic variants of SARS-CoV-2. This study provides in silico-derived mechanistic insights into the interactions of S_RBD and inhibitors, which may provide new clues for fighting SARS-CoV-2 infection.

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Cosolvent Analysis Toolkit (CAT): A Robust Hotspot Identification Platform for Cosolvent Simulations of Proteins to Expand the Druggable Proteome

10.26434/chemrxiv.7703540 ◽

2019 ◽

Author(s):

Francesc Sabanés Zariquiey ◽

Joao Victor de Souza Cunha ◽

Agnieszka K. Bronowska

Keyword(s):

Binding Sites ◽

Scoring Function ◽

Automated Analysis ◽

Md Simulations ◽

Volume Data ◽

Molecular Graphics ◽

Dynamic Interactions ◽

Wide Range ◽

High Level ◽

Graphics Software

Cosolvent Molecular Dynamics (MD) simulations are increasingly popular techniques developed for prediction and characterisation of allosteric and cryptic binding sites, which can be rendered “druggable” by small molecule ligands. Despite their conceptual simplicity and effectiveness, the analysis of cosolvent MD trajectories relies on pocket volume data, which requires a high level of manual investigation and may introduce a bias. In this work, we present CAT (Cosolvent Analysis Toolkit): an open-source, freely accessible analytical tool, suitable for automated analysis of cosolvent MD trajectories. CAT is compatible with commonly used molecular graphics software packages such as UCSF Chimera and VMD. Using a novel hybrid empirical force field scoring function, CAT accurately ranks the dynamic interactions between the macromolecular target and cosolvent molecules. To benchmark, CAT was used for three validated protein targets with allosteric and orthosteric binding sites, using five chemically distinct cosolvent molecules. For all systems, CAT has accurately identified all known sites. CAT can thus assist in computational studies aiming at identification of protein “hotspots” in a wide range of systems. As an easy-to-use computational tool, we expect that CAT will contribute to an increase of the size of the potentially ‘druggable’ human proteome.

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Effect of Resultant Dipole Moment on Mechanical Stability of Protein-Peptide Complexes

Biophysical Journal ◽

10.1016/j.bpj.2018.11.2476 ◽

2019 ◽

Vol 116 (3) ◽

pp. 459a

Author(s):

Maksim Kouza ◽

Anirban Banerji ◽

Andrzej Kolinski ◽

Irina Buhimschi ◽

Andrzej Kloczkowski

Keyword(s):

Dipole Moment ◽

Mechanical Stability ◽

Peptide Complexes

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ReflecTech® Mirror Film Attributes and Durability for CSP Applications

ASME 2009 3rd International Conference on Energy Sustainability, Volume 2 ◽

10.1115/es2009-90336 ◽

2009 ◽

Cited By ~ 3

Author(s):

Michael DiGrazia ◽

Randy Gee ◽

Gary Jorgensen

Keyword(s):

Elevated Temperatures ◽

Solar Power ◽

Mechanical Stability ◽

Uv Light ◽

Water Immersion ◽

Accelerated Testing ◽

Mechanical Resistance ◽

Test Results ◽

Concentrating Solar Power ◽

Utility Scale

Reflectors are an essential part of parabolic trough solar electric and other concentrating solar power (CSP) systems. Reflectors in CSP systems require a high reflectance over the solar wavelength spectrum and they must be durable to outdoor exposure and resist all forms of degradation over time. All utility-scale CSP systems installed to date use glass reflectors. Glass mirrors have maintained their reflectance very well in CSP environments, but they are susceptible to wind-related breakage and are expensive to transport and install. Alternative lower-cost reflectors are needed to reduce the cost of CSP systems [1]. ReflecTech® Mirror Film is a highly reflective polymer-based film co-developed with the National Renewable Energy Laboratory (NREL) for concentrating solar energy applications. The attributes of ReflecTech® Mirror Film and test results for weatherability are described herein. This paper discusses field and lab test results and properties of ReflecTech® Mirror Film, specifically: 1. Stability under ultraviolet (UV) light through accelerated testing and outdoor real-time testing. 2. Mechanical stability and resistance to moisture through water immersion tests for delamination and “tunneling”. 3. Mechanical resistance to high wind events common in utility-scale concentrating solar power applications. 4. Lighter weight and resistance to breakage that reduces transportation and installation costs, and allows greater design flexibility of concentrator geometries. 5. Lower initial cost compared with curved glass mirrors. To test for weatherability, reflector samples were subjected to controlled conditions more extreme than actual outdoor environments. NREL maintains a world-class testing capability for solar reflectors that includes a Solar Simulator (SS), QUV (an accelerated exposure chamber manufactured by Q-Lab Corp. that subjects materials to alternating cycles of light and condensation at elevated temperatures), and several WeatherOmeter® (WOM) exposure chambers that allow accelerated testing of reflector samples. In addition, samples of ReflecTech® Mirror Film have been subjected to ACUVEX® accelerated outdoor weathering tests (natural sunlight in Phoenix, AZ, concentrated 7 to 8 times with a Fresnel-reflector while the samples are cooled with a fan to near ambient conditions and sprayed with de-ionized water 8 min per natural sun hour). Immersion tests were also performed to test the resistance of ReflecTech® Mirror Film to extreme moisture. Test results compared ReflecTech® film performance to past film products like 3M’s ECP-300 and ECP-305+ which suffered from “tunneling” [2], a problem whereby the silver reflective layer delaminates from the polymer film in the presence of moisture.

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NANOGOLD decorated by pHLIP peptide: comparative force field study

Physical Chemistry Chemical Physics ◽

10.1039/c5cp01136a ◽

2015 ◽

Vol 17 (19) ◽

pp. 12648-12660 ◽

Cited By ~ 17

Author(s):

A. Kyrychenko

Keyword(s):

Force Field ◽

Field Study ◽

Force Fields ◽

Md Simulations ◽

Computational Studies ◽

Peptide Interactions

Structure of Au135 nanoparticle functionalized by pH low insertion peptide (pHLIP) compared by MD simulations based on six popular biomolecular force fields, suggesting OPLS-AA and CHARMM36 as a tool of choice for the computational studies of NANOGOLD–peptide interactions.

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Ceramic Coating Based on La, Sr and Co on Ferritic Stainless Steel for ITSOFC Interconnects

Materials Science Forum ◽

10.4028/www.scientific.net/msf.727-728.522 ◽

2012 ◽

Vol 727-728 ◽

pp. 522-527

Author(s):

Matias de Angelis Korb ◽

Raimundo Nonato Ferreira Linhares Junior ◽

Eduardo Etzberger Feistauer ◽

Ledjane Silva Barreto ◽

Vânia Caldas de Sousa ◽

...

Keyword(s):

Stainless Steel ◽

Oxidation Resistance ◽

Ferritic Stainless Steel ◽

Mechanical Stability ◽

Spray Pyrolysis Technique ◽

Alloy Coating ◽

Isothermal Oxidation ◽

Austenitic Steels ◽

Mechanical Resistance ◽

Fuel Cell Performance

Ferritic stainless steels have been used to produce interconnects for intermediate temperature solid oxide fuel cells (ITSOFC) due to their appropriate properties. Ferritic stainless steel presents mechanical stability, much higher thermal and electronic conductivities; significantly lower cost, and mechanical resistance than austenitic steels. Besides, it presents a thermal expansion coefficient compatible with the other materials of the cell components. However, in the range of this device operating temperature (600 °C 800 °C) it can occur the formation of poorly conducting oxide (Cr2O3) reducing the fuel cell performance. The aim of this work was to obtain oxide coatings starting with La, Sr and Co nitrates applied by spray-pyrolysis technique on a stainless steel AISI 430 substrate. The coatings obtained were characterized by X-ray diffraction and scanning electron microscopy/energy dispersive spectroscopy. The oxidation resistance of the ferritic stainless steel, coated with a perovskite (La0,6Sr0,4CoO3) film, was investigated by isothermal oxidation. The results showed that the coating obtained promoted the increase of the ferritic stainless steel oxidation resistance. However, after the oxidation test, it was observed a Cr enrichment and a very pronounced Sr enrichment, near to the alloy/coating interface, which can be associate to the decomposition of La0,6Sr0,4CoO3 film.

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