Detailed Molecular Dynamics Simulations Research Articles

Linagliptin and Empagliflozin Inhibit Microtubule Affinity Regulatory Kinase 4: Repurposing Anti-Diabetic Drugs in Neurodegenerative Disorders Using In Silico and In Vitro Approaches.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are significant public health burdens. Many studies have revealed the possibility of common pathophysiology between T2DM and AD. Thus, in recent years, studies deciphering the action mechanism of anti-diabetic drugs with their future use in AD and related pathologies are on high demand. Drug repurposing is a safe and effective approach owing to its low cost and time-saving attributes. Microtubule affinity regulating kinase 4 (MARK4) is a druggable target for various diseases and is found to be linked with AD and diabetes mellitus. MARK4 plays a vital role in energy metabolism and regulation and thus serves as an irrefutable target to treat T2DM. The present study was intended to identify the potent MARK4 inhibitors among FDA-approved anti-diabetic drugs. We performed structure-based virtual screening of FDA-approved drugs to identify the top hits against MARK4. We identified five FDA-approved drugs having an appreciable affinity and specificity toward the binding pocket of MARK4. Among these identified hits, two drugs, linagliptin, and empagliflozin, favorably bind to the MARK4 binding pocket, interacting with its critical residues and thus subjected to detailed analysis. All-atom detailed molecular dynamics (MD) simulations revealed the dynamics of binding of linagliptin and empagliflozin with MARK4. Kinase assay showed significant inhibition of MARK4 kinase activity in the presence of these drugs, implying them as potent MARK4 inhibitors. In conclusion, linagliptin and empagliflozin may be promising MARK4 inhibitors, which can further be exploited as potential lead molecules against MARK4-directed neurodegenerative diseases.

Evolution of energy landscapes in designer enzymes.

Bottom-up design of biocatalysts provides a unique opportunity to study how the dynamic motions of enzymes change as catalytic efficiency evolves. Using detailed biophysical and molecular dynamics simulations of enzymes designed to promote a simple proton transfer reaction, we have shown that a chemical reaction can be speeded up by modulating protein conformation landscapes to cooperatively preorganize catalytic residues to enhance transition-state stabilization while minimizing competing, unproductive conformations. Moreover, the general tightening of correlated dynamical networks that include the transition state and large parts of the protein was found to induce an activation heat capacity, leading to a non-linear temperature‑activity dependence. These findings suggest that explicit consideration of both static and dynamic computational approaches could aid the design of many de novo enzymes.

Csk αC Helix: A Computational Analysis of an Essential Region for Conformational Transitions.

Conformational changes are an essential feature for the function of some dynamic proteins. Understanding the mechanism of such motions may allow us to identify important properties, which may be directly related to the regulatory function of a protein. Also, this knowledge may be employed for a rational design of drugs that can shift the balance between active and inactive conformations, as well as affect the kinetics of the activation process. Here, the conformational changes in carboxyl-terminal Src kinase, the major catalytic repressor to the Src family of kinases, was investigated, and it was proposed as a functionally related hypothesis. A Cα Structure-Based Model (Cα-SBM) was applied to provide a description of the overall conformational landscape and further analysis complemented by detailed molecular dynamics simulations. As a first approach to Cα-SBM simulations, reversible transitions between active (closed) and inactive (open) forms were modeled as fluctuations between these two energetic basins. It was found that, in addition to the interdomain Carboxyl-terminal SRC Kinase (Csk) correlated motions, a conformational change in the αC helix is required for a complete conformational transition. The result reveals this as an important region of transition control and domain coordination. Restrictions in the αC helix region of the Csk protein were performed, and the analyses showed a direct correlation with the global conformational changes, with this location being propitious for future studies of ligands. Also, the Src Homology 3 (SH3) and SH3 plus Src Homology 2 (SH2) domains were excluded for a direct comparison with experimental results previously published. Simulations where the SH3 was deleted presented a reduction of the transitions during the simulations, while the SH3-SH2 deletion vanishes the Csk transitions, corroborating the experimental results mentioned and linking the conformational changes with the catalytic functionality of Csk. The study was complemented by the introduction of a known kinase inhibitor close to the Csk αC helix region where its consequences for the kinetic behavior and domain displacement of Csk were verified through detailed molecular dynamics. The findings describe the mechanisms involving the Csk αC helix for the transitions and also support the dynamic correlation between SH3 and SH2 domains against the Csk lobes and how local energetic restrictions or interactions in the Csk αC helix can play an important role for long-range motions. The results also allow speculation if the Csk activity is restricted to one specific conformation or a consequence of a state transition, this point being a target for future studies. However, the αC helix is revealed as a potential region for rational drug design.

The viscosity of liquid ethene: Measurement and molecular dynamic simulation

This work reports new experimental data and detailed equilibrium molecular dynamics (EMD) simulations of viscosity for liquid ethene. The measurements were carried out by using an improved vibrating-wire viscometer for temperatures from (173.150 to 233.150) K and pressures up to 5.5 MPa, with a combined expanded relative uncertainty of 5.3 % (k = 2). The experimental data were compared with the values calculated by the correlation of Holland et al. (with an uncertainty of 10 % for liquid), the deviations vary from − 7.2 % to 0.8 % and the AARD is 3.6 %. Furthermore, the Assael and Dymond scheme based on the hard-sphere model was used to correlate the experimental results with an AARD of 0.1 %. For understanding the structure and properties of liquid ethene at the molecular level, a comprehensive evaluation of ten different ethene force fields with four types of molecular configurations (two-site, three-site, four-site, and six-site models) was then performed to predict density and viscosity at a wide temperature range from (133.150 to 233.150) K and pressure of 5 MPa. The selected force fields were generally developed for the vapor–liquid equilibrium properties, without explicit consideration of viscosity and other transport properties. Overall, three rigid two-site force fields (SET, TraPPE-UA, and AUA4) gave the best predictions with the AARD within 0.32 % for density and 8.5 % for viscosity comparing with the correlations of Smukala et al. and Holland et al., separately. Mie force field with 16–6 potential and TraPPE-UA2 force field with two negative partial charges can accurately predict density but severely overestimate viscosity greater than 20 %. The larger intermolecular repulsion and electrostatic interaction may have contributed to the overestimation of viscosity especially at low temperatures.

Impact tension behavior of heavy-drawn nanocrystalline CoCrNi medium entropy alloy wire

High-strength metallic wire is a vital bearing structure used in many industrial fields. Impact loads often challenge the service safety of metal wire in engineering applications. However, few studies have been made on the dynamic mechanical behavior of metallic wires, especially for newly developed high-entropy alloy wires. By equipping split Hopkinson tension bar (SHTB) with specially designed test fixtures, we have carried out a systematic study on the dynamic deformation behavior of the heavily-drawn CoCrNi medium-entropy alloy (MEA) wire in impact tension at both room and cryogenic temperatures. We show that these millimeter-diameter MEA wires with nano-scale grains can achieve an excellent combination of impact tensile strength and ductility at 293 K and 77 K. More interestingly, we find that the strength and ductility of the MEA wire were enhanced simultaneously with decreasing temperature and increasing strain rate. Detailed microstructure characterizations and molecular dynamics simulations reveal that the increased strength and ductility at coupled high strain and low temperature resulted from the multiplication and thinning of nanoscale twins, which further caused additional strengthening and toughening mechanisms such as stack faulting net and secondary twin. This study highlights the advantage of CrCoNi MEA wire for cryogenic temperature and impact applications and provides an experimental reference for the design and evaluation of high-strength metal wires under such extreme conditions.

Mechanical Behavior of Polymer Nanocomposites via Atomistic Simulations: Conformational Heterogeneity and the Role of Strain Rate.

Polymer nanohybrids with a high fraction of nanofillers have been found to exhibit improved mechanical properties compared to the neat polymer homogeneous systems. Since polymer-based materials are characterized by a broad range of relaxation times, it is expected that their response under external load would depend on the actual rate of the applied deformation. In this work, we investigate the heterogeneous mechanical behavior in glassy poly(ethylene oxide)/silica nanoparticles (PEO/SiO2) nanocomposites via detailed atomistic molecular dynamics simulations. Our goal is to unravel the effect of strain rate on the mechanism of polymer nanocomposite reinforcement, within the glassy state, by directly probing the mechanical properties at the molecular level. By applying tensile deformations with various strain rates we clearly demonstrate that the value of the applied strain rate strongly affects the mechanical properties of the PEO/SiO2 model systems, inducing a transition from a rubber-like behavior, at low strain rate, to a more brittle one, at high strain rates. Then, we further investigate the mechanical heterogeneity in glassy PEO/SiO2 systems by probing directly the stress and strain fields for various conformations of adsorbed (trains, tails, loops, and bridges), and free polymer chains. Our data emphasize the importance of both train and bridge conformations on the mechanical reinforcement of the polymer nanocomposites. Last, we also probe the mobility of various chain conformations, under different applied strain rates, and their contribution to the overall mechanical behavior of the nanocomposite, during the deformation process.

Accelerated Diffusion Following Deprotection in Chemically Amplified Resists.

Polymeric chemically amplified resists (CARs) are critical materials for high-throughput lithographic processes. A photoactivated acid-anion catalyst changes the polymer's solubility via a deprotection reaction, which enables pattern development through selective dissolution. To capture observed reaction kinetics, reaction-diffusion models employ a catalyst diffusivity that is accelerated by reaction. However, the microscopic origin and factors contributing to this phenomena remain unclear. Herein, we employ detailed atomistic molecular dynamics simulations to examine the impact of protecting group removal and material relaxation on catalyst mobility. We report data on polymer density, catalyst dispersion, excess free volume, and segmental dynamics with increasing time/extent of deprotection. We then propose simple kinetic Monte Carlo algorithms that can describe both molecular dynamics simulations of deprotection reactions and experimental data.

Atomistically-informed modeling of point defect clustering and evolution in irradiated ThO2

A cluster dynamics (CD) model has been developed to investigate the nucleation and growth of point defect clusters, i.e., interstitial prismatic loops and nanoscale and sub-nanoscale voids, in ThO2 during irradiation by energetic particles. The model considers cluster off-stoichiometry due to the asymmetry of point defect generation on the O and Th sublattices under irradiation, as well as the point defect diffusivities and the defect binding energies to clusters. The energies were established using detailed molecular dynamics simulations considering the statistical variability of cluster configuration. A high-order adaptive time-integration has been used to solve the model. The predicted loop density and their average size is in good agreement with reported experimental observations for proton irradiated ThO2 at 600°C. The model did not predict void evolution due to the sluggish kinetics of cation vacancies, explaining the absence of voids in proton irradiated ThO2 (and other oxides) at relatively low temperatures.

Characterization and computational simulation of human Syx, a RhoGEF implicated in glioblastoma.

Structural discovery of guanine nucleotide exchange factor (GEF) protein complexes is likely to become increasingly relevant with the development of new therapeutics targeting small GTPases and development of new classes of small molecules that inhibit protein‐protein interactions. Syx (also known as PLEKHG5 in humans) is a RhoA GEF implicated in the pathology of glioblastoma (GBM). Here we investigated protein expression and purification of ten different human Syx constructs and performed biophysical characterizations and computational studies that provide insights into why expression of this protein was previously intractable. We show that human Syx can be expressed and isolated and Syx is folded as observed by circular dichroism (CD) spectroscopy and actively binds to RhoA as determined by co‐elution during size exclusion chromatography (SEC). This characterization may provide critical insights into the expression and purification of other recalcitrant members of the large class of oncogenic—Diffuse B‐cell lymphoma (Dbl) homology GEF proteins. In addition, we performed detailed homology modeling and molecular dynamics simulations on the surface of a physiologically realistic membrane. These simulations reveal novel insights into GEF activity and allosteric modulation by the plekstrin homology (PH) domain. These newly revealed interactions between the GEF PH domain and the membrane embedded region of RhoA support previously unexplained experimental findings regarding the allosteric effects of the PH domain from numerous activity studies of Dbl homology GEF proteins. This work establishes new hypotheses for structural interactivity and allosteric signal modulation in Dbl homology RhoGEFs.

Will Polycrystalline Platinum Tip Sliding on a Gold(111) Surface Produce Regular Stick–Slip Friction?

Friction measurements by an atomic force microscope (AFM) frequently showed regular stick-slip friction signals with atomic-scale resolutions. Typically, for an AFM metal tip sliding on a metal crystal surface, the microstructure of the tip made from the thermally evaporated metal coating on a silicon cantilever was polycrystalline. Our detailed molecular dynamics(MD) simulations of a polycrystalline Pt tip (R = 10 nm in radius) sliding on an Au(111) surface revealed how the geometry of the polycrystalline tip took effect on the friction behavior at the contact interface. We found that the apex of the Pt tip with multiple grains near the edge of contact could induce severe plastic deformations of the gold substrate, leading to irregular stick-slip frictions upon sliding. Simulation results showed that in order to achieve a clear stick-slip friction signal with single atomic slips, the apex of the Pt tip must adopt a single crystalline protrusion without any neighboring grains involved in the metal contact. We showed that such a single crystalline protrusion, which presumably could be achieved during initial run-in or wear-out of high-energy Pt atoms in the neighboring grains, was passivated by a large number of gold atoms due to metal adhesion in the contact periphery. Using such a crystalline protrusion tip, we demonstrated that the stick-slip friction produced was very "tolerant" to the adhesion of a large number of gold atoms on the tip apex. We further showed that AFM tip mass used in MD simulations also played an important role in determining the transition between friction regimes, which could be well explained by the Prandtl-Tomlinson thermal activation model.

Binding Interactions between Receptor-Binding Domain of Spike Protein and Human Angiotensin Converting Enzyme-2 in Omicron Variant.

The emergence of new SARS-CoV-2 Omicron variant of concern (OV) has exacerbated the COVID-19 pandemic because of a large number of mutations in the spike protein, particularly in the receptor-binding domain (RBD), resulting in highly contagious and/or vaccine-resistant strains. Herein, we present a systematic analysis based on detailed molecular dynamics (MD) simulations in order to understand how the OV RBD mutations affect the ACE2 binding. We show that the OV RBD binds to ACE2 more efficiently and tightly predominantly because of strong electrostatic interactions, thereby promoting increased infectivity and transmissibility compared to other strains. Some of the OV RBD mutations are predicted to affect the antibody neutralization either through their role in the S-protein conformational changes, such as S371L, S373P, and S375F, or through changing its surface charge distribution, such as G339D, N440K, T478K, and E484A. Other mutations, such as K417N, G446S, and Y505H, decrease the ACE2 binding, whereas S447N, Q493R, G496S, Q498R, and N501Y tend to increase it.

Mechanical properties of glassy polymer nanocomposites via atomistic and continuum models: The role of interphases

The mechanical properties of glassy polymer nanocomposites (PNCs) are investigated via a new hierarchical computational methodology, which combines atomistic molecular dynamics (MD) simulations and homogenization approaches. The homogenization methodology is based on a systematic nano/micro/macro coupling between detailed atomistic MD simulations and a variational approach through the Hill–Mandel lemma. The proposed methodology is applied in model glassy polybutadiene/silica nanocomposites for different nanoparticle (NP) volume fractions. Initially, using MD simulations, the polymer/NP interphase in PNCs is directly examined by probing the density distribution and the stress profile at equilibrium. By using a continuum mechanics based approach, we can compute effective deformation gradients for each atom, allowing us to probe the distribution of the (local) stress and strain fields in the atomistic model. With this new approach, the effective Young modulus and the Poisson ratio of the polymer/NP interphases are directly calculated, exhibiting a higher rigidity compared to the polymer matrix. In the last part of the proposed approach, the mechanical properties at the interphases and the polymer are used together with the homogenization approach to develop a continuum model for predicting the mechanical properties of the PNCs, which are found to be in very good agreement with the effective mechanical properties calculated through atomistic MD simulations.

Why Do Liquids Mix? The Mixing of Protic Ionic Liquids Sharing the Same Cation Is Apparently Driven by Enthalpy, Not Entropy.

We study hydrogen bond (HB) redistribution in mixtures of two protic ionic liquids (PILs) sharing the same cation: triethylammonium methanesulfonate ([TEA][OMs]) and triethylammonium trifluoromethanesulfonate ([TEA][OTf]). The mixtures exhibit large negative energies of mixing. Based on results obtained from atomic detail molecular dynamics (MD) simulations, we derive a lattice model, discriminating between HB and nonspecific intermolecular interactions. We demonstrate that due to the ordered structure of the PILs, mostly the HB interactions contribute to the mixing energy. This allows to us to connect the equilibrium of HBs to each of the two anion species with the corresponding excess energies and entropies. The entropy associated with HB redistribution is shown to be negative, and even overcompensating the positive entropy associated with a statistical distribution of the ions in the mixture. This is strongly suggesting that the mixing process is driven by enthalpy, not entropy.

Synergistic effect of electric field and temperature on POSS modified natural ester insulating oil: A molecular dynamics study

The use of nano-materials can effectively improve the dielectric and heat transfer properties of natural ester insulating oil. However, the migration and interaction mechanism of components in nano-modified insulating oil under electric field is still not clear. Through detailed Molecular Dynamics (MD) simulation, this study revealed the migration and interaction mechanism of Cage Polysilsesquioxane (POSS) and H2O molecules in natural ester insulating oil. The data indicates that POSS and H2O molecules have completely different diffusion properties under electric field. The existence of electric field not only makes the displacement of molecules nonlinear, but also limits the Brownian motion of H2O molecules. On the contrary, POSS molecules under electric field have better diffusion properties. Electric field leads to the extremely uneven distribution of electrostatic potential (ESP) of oil molecules, which makes it easier for H2O molecules with small volume to dissociate near the polarized oil molecular structure and be bound by it, and the interaction energy between oil molecules and POSS molecules under the action of electric field will be weakened, which is the main reason why H2O and POSS molecules have completely different diffusion performance under electric field. The limited displacement of H2O molecules can inhibit the aging of insulating oil and improve its service life. Compared with the electric field effect, temperature has a great influence on the interaction energy between POSS and oil molecules. The results provide useful guidance for the design of the next generation of natural ester nano-modified insulating oil.

Merging structural frameworks of imidazolium, pyridinium, and cholinium ionic liquids with cinnamic acid to tune solution state behavior and properties

Solubility in water, interactions with the solvent medium and tuning of molecular conformation in the liquid phase are the key issues to discover new biologically active molecules and to understand the mechanisms of their action. In the present article, we report synthesis, structural and biological activity studies, and computational modeling of new ionic compounds. Structural frameworks of well-known imidazolium, pyridinium and cholinium ionic liquids (ILs) were combined with naturally occurring cinnamic acid (CA), which is known to possess a wide spectrum of biological activity. Different combinations of these two structural elements (IL and Cin (cinnamic moiety)) allowed modulating the solubility, physicochemical properties and biological activity of the resulting molecules. A significant increase in the biological activity was achieved for the three studied hybrid molecules - [C4mim-Cin][Cl], [C4py–Cin][Cl], and [C4mim-Cin][Cin]. Multiparameter cytotoxicity mapping was performed to visualize the biological activity of the 28 studied molecules. Detailed experimental investigation and molecular dynamics simulation were performed to gain insight into the structure–activity relationship. Of note, a folding conformational change in the structure of [Cnmim-Cin][Cl] hybrid molecules in solution resulted in a substantial change in chemical reactivity, with the activation energy of the hydrolysis reaction decreasing from 32.1 to 23.9 kcal/mol.

Host cell membrane capture by the SARS-CoV-2 spike protein fusion intermediate

Cell entry by SARS-CoV-2 is mediated by the Spike (S) protein. Following binding of the S1 subunit to ACE2 receptors and release of the S2 subunit, S2 undergoes a structural transition to its potent, fusogenic form, the extended fusion intermediate (FI). The FI captures the target cell membrane and subsequently refolds and fuses the membrane with the viral envelope to facilitate cell entry, but the mechanisms are not established. The FI structure is unknown and detailed molecular dynamics (MD) simulations are unavailable, hindering the search for FI-targeting drugs.

Lessons Learned from Responsive Molecular Dynamics Studies of the COVID-19 Virus.

Over the past 18 months, the need to perform atomic detail molecular dynamics simulations of the SARS-CoV-2 virion, its spike protein, and other structures related to the viral infection cycle has led biomedical researchers worldwide to urgently seek out all available biomolecular structure information, appropriate molecular modeling and simulation software, and the necessary computing resources to conduct their work. We describe our experiences from several COVID-19 research collaborations and the challenges they presented in terms of our molecular modeling software development and support efforts, our laboratory's local computing environment, and our scientists' use of non-traditional HPC hardware platforms such as public clouds for large scale parallel molecular dynamics simulations.

Polymer-Surfactant Driven Interactions and the Resultant Microstructure in Protein-Containing Liquid Crystal Droplets.

Integration of molecular liquid crystals (LCs) with functional proteins can provide new class of materials for potential applications in optical biosensing. However, hydrophobic nematic LCs (length ∼ 1-2 nm) and hydrophilic proteins, size ∼ O (nm), do not intermix without chemical modification of at least one of them. Bioconjugation of proteins with a polyethylene glycol-based polymeric surfactant (PS) can provide a core-shell system that is sequestered within nonaqueous LC (4-cyano-4'-pentylbiphenyl) microdroplets. However, the nature of interactions between the components and detailed understanding of the resultant hybrid microstructure remains unclear. Here, using a combination of isothermal titration calorimetry (ITC), fluorescence microscopy, and infrared-imaging spectroscopy, we show that strong hydrophobic interactions between the LC and PS drives the sequestration of a myoglobin-PS (Mb-PS; dispersed in the aqueous phase) into the LC spherical microdroplets or even into a bulk LC phase. The average values of both, the binding constant and the standard molar enthalpy change, are increased by approximately a factor of 2.5 times when the unmodified Mb is conjugated to the PS. Small-angle X-ray scattering studies reveal that LC molecules act as a solvent for the Mb-PS conjugate; furthermore, the LC long-range order is disturbed due to mixing, as exemplified by the change in its coherence length from 8.9 to 5.7 nm. Detailed all-atomistic molecular dynamic simulations for a three-component PS-water-LC system show a change in interaction energy of -144 kJ mol-1 PS-1 upon the contact of PS chains (initially dispersed in water) with LC and agree with the ITC experiments.

The dual role of phytochemicals on SARS-CoV-2 inhibition by targeting host and viral proteins

BackgroundThe severe acute respiratory syndrome-2019 has affected more than 190 million people around the world and caused severe crises throughout the globe. Due to rapid mutation in the viral genome, its became important to simultaneously improvise the host immunity while targeting viral proteins to reduce the severity of infection. AimThe current computational work focuses on multi-level rigorous screening of 47 medicinal plant-based phytochemicals for discovering effective phytochemical inhibitors against the host and viral targets. Experimental procedureA total of 586 phytochemicals were analyzed in detail based on their drug-likeness, pharmacological properties, and structure-based activity against the viral proteins (Spike glycoprotein, Papain-like protease, and Main protease) and host proteins (ACE2, Importin-subunit α-5, and β-1). Phytochemicals showing higher binding affinity with the dual capacity to target both the categories of proteins were further analyzed by profiling of their chemical reactivity using Density-Functional Theory (DFT) based quantum chemical methods. Finally, detailed molecular dynamics simulations were performed to analyze the interactions of the complexes. Results and conclusionThe results revealed that the selected phytochemicals from Andrographis paniculata, Aconitum heterophyllum, Costus speciosus and Inula racemosa may have the capacity to act with prominent affinity towards the host and viral proteins. Therefore, the combination of active phytochemicals of these plants may prove to be more beneficial and can be used for developing the potential phytotherapeutic intervention.

Structure and Dynamics of Highly Attractive Polymer Nanocomposites in the Semi-Dilute Regime: The Role of Interfacial Domains and Bridging Chains.

Detailed molecular dynamics (MD) simulations are employed to study how the presence of adsorbed domains and nanoparticle bridging chains affect the structural, conformational, thermodynamic, and dynamic properties of attractive polymer nanocomposite melts in the semi-dilute regime. As a model system we have chosen an unentangled poly(ethylene glycol) (PEG) matrix containing amorphous spherical silica nanoparticles with different diameters and at different concentrations. Emphasis is placed on properties such as the polymer mass density profile around nanoparticles, the compressibility of the system, the mean squared end-to-end distance of PEG chains, their orientational and diffusive dynamics, the single chain form factor, and the scattering functions. Our analysis reveals a significant impact of the adsorbed, interfacial polymer on the microscopic dynamic and conformational properties of the nanocomposite, especially under conditions favoring higher surface-to-volume ratios (e.g., for small nanoparticle sizes at fixed nanoparticle loading, or for higher silica concentrations). Simultaneously, adsorbed polymer chains adopt graft-like conformations, a feature that allows them to considerably extend away from the nanoparticle surface to form bridges with other nanoparticles. These bridges drive the formation of a nanoparticle network whose strength (number of tie chains per nanoparticle) increases substantially with increasing concentration of the polymer matrix in nanoparticles, or with decreasing nanoparticle size at fixed nanoparticle concentration. The presence of hydroxyl groups at the ends of PEG chains plays a key role in the formation of the network. If hydroxyl groups are substituted by methoxy ones, the simulations reveal that the number of bridging chains per nanoparticle decreases dramatically, thus the network formed is less dense and less strong mechanically, and has a smaller impact on the properties of the nanocomposite. Our simulations predict further that the isothermal compressibility and thermal expansion coefficient of PEG-silica nanocomposites are significantly lower than those of pure PEG, with their values decreasing practically linear with increasing concentration of the nanocomposite in nanoparticles.