GROMOS 43A1 Force Field Research Articles

Models of the Three-Component Bilayer of Stratum Corneum: A Molecular Simulation Study.

The construction of the stratum corneum (SC) is crucial to the problems of transdermal drug delivery. SC consists of the keratinocyte layers and the lipid matrix surrounding it. Among them, the lipid matrix is the barrier for many exogenous molecules, mainly composed of ceramides (CERs), free fatty acids (FFA), and cholesterol (CHOL). In this work, we developed single-component (CERs, CER-NS, and CER-EOS) and six three-component models, and each model was simulated by using the GROMOS-54A7 force field. Short-period phase (SPP) and long-period phase (LPP) systems were established separately, and area per lipid (APL), thickness, order of carbon chain (SCD), and density distribution were analyzed. The transition of CER-NS and CER-EOS in LPP was observed. The results of hydrogen bonds in the lipid systems indicated that a strong hydrogen-bond network was formed between the skin-lipid bilayers. Umbrella sampling method simulations were performed to calculate the free energy change of ethanol moving into the skin-lipid bilayer. The results revealed that ethanol molecules pulled some water molecules into the membrane when they passed through SPP-1. Our findings provided some insights and models of the stratum corneum that could be used for the subsequent mechanism of macromolecule permeation through membranes in drugs, cosmetics, and so on.

Influence of degree of substitution on the hydroxypropyl-β-cyclodextrin complexation with rifampicin in water solution: a molecular simulation.

Hydroxypropyl-β-cyclodextrin (HPβCD) is one of the derivatized cyclodextrins most widely used as an excipient in the pharmaceutical industry, for its capacity to improve certain drugs properties. Different configurations of HPβCD are possible depending on the number and location of the 2-hydroxypropyl groups substituted on the glucose rings. Rifampicin has become the most commonly clinically used antibiotic against tuberculosis in recent years, despite its low solubility and variable bioavailability. Different techniques and materials have been proposed to enhance the properties of rifampicin: cyclodextrin complexation is one of them. The van der Waals term was the main contribution to the interaction energy, which then decisively conditioned the complex configurations. The size of rifampicin did not allow the whole molecule to fit into the host. Moreover, interaction energy was much greater when the guest was located near each rim of HPβCD, where rifampicin was partially included in the cavity and formed inclusion complexes. The piperazine tail of rifampicin was included inside the host in minimum energy structures and the guest was situated near the primary rim of HPβCD in most cases, although the complex configurations depended on the degree of substitution. A molecular mechanics simulation based on the GROMOS 53A6 force field was applied in this work to study the inclusion complexes formed by twelve configurations of HPβCD, with different degrees of substitution and rifampicin in water solution. We determined the penetration potential, the complex structures with minimum energies, the possibility of forming inclusion complexes other than those of minimum energies and potential energy surfaces.

The Study of the Binding Ability of Antimicrobial Peptides to Spike Protein of the Coronavirus by Docking and Molecular Dynamics Simulation

Introduction: Since the start of 2020, SARS -CoV-2 has infected a significant number of individuals, prompting extensive research. Antimicrobial peptides can be considered as a promising treatment for emerging viral pathogens due to their safety, efficacy, and specificity. Method: In this study, first, 104 natural antiviral peptides were chosen from APD databases. Then, the third structure of proteins was modeled by PEP -FOLD 3 server. The structures were refined and optimized for docking operation. Subsequently, peptide -protein docking was performed using AutoDock Vina. The most favorable peptide -protein complex, chosen based on binding energy, was employed for molecular simulation using GROMACS. The simulation was carried out for 100 ns at 310° K and pH=7. Gromos54a7 force field was used in this study and the SPC water model was used as solvent. Results: The obtained results from molecular dynamics examine the stability of complex structure and energy calculations. RMSD, RMSF, radius of gyration, and SASA analyses indicate the stability of the peptide -protein complex during the simulation. Additionally, LJ, CL, HBond, and ΔG analyses were conducted to calculate the energy interactions between the peptide and the Spike protein. Conclusion: The results indicate that antimicrobial peptides can effectively bind to the SARS -CoV-2 spike protein, acting as inhibitors with a favorable binding energy. Consequently, these peptides can be employed for therapeutic and experimental studies of COVID -19.

Evaluation of the affinity of asphaltene molecular models A1 and A2 by the water/oil interfaces based on a novel concept of solubility parameter profiles obtained from MD simulations

Crude oils are formed of asphaltenes that are species soluble in certain solvents such as toluene. The distribution of asphaltene models and their mixtures in water/n–heptane and water/toluene systems were explored with MD simulations. A1 and A2 asphaltene models were used for the exploration of the affinity of these compounds by the water/oil interfaces. For this, a novel concept called solubility parameter profiles was used to characterize the polarity of the regions present in water/n–heptane and water/toluene systems. Molecules of asphaltene models, n–heptane, and toluene were described with the GROMOS53A6 force field and CHELPG atomic charges, and water molecules with the SPC model. The prediction of the affinity of A1 and A2 asphaltene models at interfaces was determined using the total solubility parameter differences calculated between these species and solvent molecules. Calculated solubility parameters show a good correlation with experimental values. Total solubility parameter differences equal to Δδtotal = 3.76 MPa0.5 and Δδtotal = 0.36 MPa0.5 at the water/n–heptane interface suggest that asphaltene models have a good affinity by the water/n–heptane interface in comparison with the water/toluene interface whose values were Δδtotal = 5.82 MPa0.5 and Δδtotal = 9.94 MPa0.5 for A1 and A2 asphaltene models, respectively. It was demonstrated that the affinity of asphaltenes by a specific region of the immiscible system is controlled by the electrostatic and dispersive contributions associated with the solubility parameter profiles.

MODELLING OF ZAP-70 ACTIVATION UPON PHOSPHORYLATION OF TYR315, TYR319 AND TYR493 FOR SIGNALLING T-CELL ACTIVATION

<h3>Introduction</h3> ZAP–70 is a key kinase in the regulation of the adaptive immune response. Zap-70 acts by binding its SH2-domains to T-cell-associated CD3ζ protein, thus transmitting T-cell activation signals induced by the interaction of Major Histocompatibility Complexes with T-cell Receptors. Phosphorylation of Tyr315, Tyr319 and Tyr 493 is required for ZAP-70 kinase activation by unclear mechanisms. In this study tools of structural bioinformatics were used to elucidate the mechanisms of ZAP-70 activation. <h3>Methods</h3> The consequences of the phosphorylation of Tyr315, Tyr319, Tyr493 were studied using 300 ns Molecular Dynamics simulations with GROMACS software and GROMOS 54a7 forcefield allowing assessment of phosphorylated tyrosines. <h3>Results</h3> The atomic structure of full-length nonphosphorylated ZAP-70 was first predicted to be next used in MD-simulations. The simulations show that phosphorylation of Tyr315, Tyr319, Tyr493 stabilizes ZAP-70 activation loop through the formation of hydrogen bonds of pTyr493 with Asp489 and Asp490, as well as through salt bridge formation between pTyr493 and Arg460. These results suggest that this stabilization of the ZAP-70 kinase domain activation loop allows the subsequent phosphorylation of LAT and SLP-76 by ZAP-70. <h3>Conclusion</h3> According to this scenario, the role of phosphorylation of Tyr315 and Tyr319 is in the separation of N-SH2 and C-SH2 domains through distance providing space complementarity between ZAP-70 and CD3ζ dimer ITAM-motives which results in ZAP-70 recruitment to T-cell membranes where phosphorylation of Tyr493 by Lck-kinase occurs.

Molecular dynamics simulations of the permeation and distribution of plasma ROS in aquaporin-1

In recent years, cold atmospheric plasma (CAP) has been found to induce apoptosis selectively in cancer cells and has become a research hotspot, but the underlying mechanisms remain unclear. Aquaporins (AQPs) on the cell membranes of cancer cells are believed to be related to the selective therapeutic mechanism of CAP. In this study, the reactive oxygen species (ROS) generated by CAP, which are believed to play an important role in the apoptosis of cancer cells, crossed the membrane through aquaporin-1 (AQP1). The process of membrane penetration, the distribution of ROS on the membrane, and the free energy barrier of AQP1 on ROS are determined by the molecular dynamics simulation based on the GROMOS 53A6 force field. The ROS distribution shows that the presence of AQP1 results in a deeper distribution of hydrophilic ROS in cell membranes. The free energy barrier for the movement of hydrophilic ROS through AQP1 is significantly lower than that for their movement through the lipid bilayer. Therefore, AQP1 on the cell membrane can improve the efficiency of the entry of hydrophilic ROS into cancer cells. These results illustrate that AQP1 can improve the transmembrane efficiency of ROS and provide insights into the mechanism underlying the selectivity of CAP at the atomic level.

Molecular Dynamics Modeling of Surfactant Block Copolymer Catalysis of Protein Disaggregation and Refolding

While hydrophilic polymers like polyethylene glycol (PEG) must be used at toxic concentrations to restore catalytic activity of heat denatured lysozyme, low molar ratios of poloxamer 188 (P188), an amphiphilic polymer, can recover up to 85% of its catalytic activity. The interactions that facilitate the poloxamer-mediated protein refolding response remain unclear. Molecular simulations using heat denatured lysozyme with P188 and PEG of the same molecular weight illustrate the importance of amphiphilicity. All MD simulations were performed using GROMACS version 2020.3 and the Protein Data Bank's lysozyme structure (1AKI.pdb). The GROMOS 53A6 force field was adapted by Max Berkowitz's Lab at UNC to account for experimentally observed behavior of α,w-dimethoxypolyethylene glycol in aqueous solutions. P188 was compared to a PEG chain of approximately the same molecular mass (8400 Daltons). The simulations were conducted at physiological conditions for up to 20 ns. The radius of gyration, root mean square deviance, and root mean square fluctuations were calculated to relate changes in the compactness of the protein to the relative amount of polymer-protein interactions. The radial distribution showed an increase in the density of the first hydration shell with P188 treatment that was not seen with PEG. By interacting with exposed hydrophobic domains of the protein, the hydrophobic block of P188 brings the hydrophilic arms of the polymer in proximity to the protein's first hydration shell. These results indicate that the presence of the hydrophobic domain is essential to a copolymer surfactant's capability to disaggregate a particular unfolded protein. These copolymer-protein aggregate interactions provide very meaningful insight into molecular design constraints for the engineering of synthetic chaperones.

Diffusion of oxytocin in water: a molecular dynamics study

Classical molecular dynamics simulation is performed to estimate the diffusion coefficient of oxytocin in water at different temperatures, 288 K, 300 K, 313 K, 323 K, using GROningen Machine for Chemical Simulations (GROMOCS). The simulation is carried out using GROMOS43A1 force field and extended simple point charge (SPC/E) water model. The stability of the system is evaluated from energy profile of potential and kinetic energy, which assures well equilibrated molecular system. The self-diffusion coefficient of oxytocin and water is obtained from Einstein’s relation and binary diffusion coefficient is obtained from Darken’s relation. As temperature increases the diffusion coefficient also increases as per expectation. The diffusion coefficients of water from the present calculations agree well with the previously reported values, within the 10% of deviation. Furthermore, the activation energy has been studied using Arrhenius Plot.&#x0D; BIBECHANA 18 (2021) 108-117

Improved GROMOS 54A7 Charge Sets for Phosphorylated Tyr, Ser, and Thr to Deal with pH-Dependent Binding Phenomena

Phosphorylation is a ubiquitous post-translational modification in proteins, and the phosphate group is present constitutively or transiently in most biological building blocks. These phosphorylated biomolecules are involved in many high-affinity binding/unbinding events that rely predominantly on electrostatic interactions. To build accurate models of these molecules, we need an improved description of the atomic partial charges for all relevant protonation states. In this work, we showed that the commonly used protocols to derive atomic partial charges using well-solvated molecules are inadequate to model the protonation equilibria in binding events. We introduced a protocol based on PB/MC calculations with a single representative conformation (of both protonation states) and used the resulting pKa estimations to help manually curate the atomic partial charges. The final charge set, which is fully compatible with the GROMOS 54A7 force field, proved to be very effective in modeling the protonation equilibrium in different phosphorylated peptides in the free (tetrapeptides, pentapeptides, and pY1021) and protein-complexed forms (pY1021/PLC-γ1 complex). This was particularly important in the case of the pY1021 bound to the SH2 domain of PLC-γ1, where only our curated charge set captured the correct protonation equilibrium at the neutral to slightly acidic pH range. The binding/unbinding phenomena in that pH range are biologically relevant, and to improve our models, we need to go beyond the commonly used protocols and obtain revised force field parameters for these molecules.

Structural and molecular bases of angiotensin-converting enzyme inhibition by bovine casein-derived peptides: an in silico molecular dynamics approach

The angiotensin-converting enzyme (ACE) plays a key role in blood pressure regulation process, and its inhibition is one of the main drug targets for the treatment of hypertension. Though various peptides from milk proteins are well-known for their ACE-inhibitory capacity, research devoted to understand the molecular bases of such property remain scarce, specifically for such peptides. Therefore, in this work, computational molecular docking and molecular dynamics calculations were performed to enlighten the intermolecular interactions involved in ACE inhibition by six different casein-derived peptides (FFVAPFPEVFGK, FALPQYLK, ALNEINQFYQK, YLGYLEQLLR, HQGLPQEVLNENLLR and NAVPITPTLNR). Two top ranked docking poses for each peptide (one with N- and the other C-terminal peptide extremity oriented towards the ACE active site) were selected for dynamic simulations (50 ns; GROMOS53A6 force field), and the results were correlated to in vitro ACE inhibition capacity. Two molecular features appeared to be essential for peptides to present high ACE inhibition capacity in vitro: i) to interact with the S1 active site residues (Ala354, Glu384, and Tyr523) by hydrogen bonds; ii) to interact with Zn2+ coordinated residues (His383, His387, and Glu411) by short-lenght hydrogen bonds, as observed in the cases of ALNEINQFYQK (IACE = 80.7%), NAVPITPTLNR (IACE = 80.7%), and FALPQYLK (IACE = 79.0%). Regardless of the temporal stability of these strong interactions, they promoted some disruption of Zn2+ tetrahedral coordination during the molecular dynamics trajectories, and were pointed as the main reason for the greatest ACE inhibition by these peptides. On the other hand, peptides with intermediate inhibition capacity (50% < IACE < 45%) interacted mainly by weaker interactions (e.g.: electrostatic and hydrophobic) with the Zn2+ coordinated residues, and were not able to change significantly its tetrahedral coordination structure. These findings may: i) assist the discrimination in silico of “good” and “bad” ACE-inhibitory peptides from other food sources, and/or ii) aid in designing de novo new molecules with ACE-inhibitory capacity. Communicated by Ramaswamy Sarma

A new analogue of islet neogenesis associated protein with higher structural and plasma stability

Islet Neogenesis Associated Protein pentadecapeptide (INGAP-PP) increases β-cell mass and function in experimental animals. A short clinical trial also yielded promising results. However, HTD4010, a new peptide derived from INGAP-PP, was developed in order to optimize its specific effects by minimizing its side effects. To study and compare the tertiary structure, stability dynamics, and plasma stability of HTD4010, an INGAP-PP analogue. Both peptides were pre-incubated in human, rat and mouse plasma at 37 °C, and their presence was identified and quantified by high performance liquid chromatography at different time-points. GROMACS 2019 package and the Gromos 54A7 force field were used to evaluate overall correlated motion of the peptide molecule during molecular dynamics simulation by essential dynamics. HTD4010 exhibited significantly larger plasma stability than INGAP-PP, and its structural stability was almost 3.36-fold higher than INGAP-PP. These results suggest that HTD4010 may facilitate longer tissue interaction, thereby developing higher potential biological effects. If so, HTD4010 may become a promising therapeutic agent to treat people with diabetes. Communicated by Ramaswamy H. Sarma

A multiscale study of the penetration-enhancing mechanism of menthol

Abstract Objective Transdermal drug delivery systems represent a critical focus in the pharmaceutics field; however, their use is limited by the fact that many drugs usually pass through the skin with low permeability. Menthol is a common penetration enhancer because of its high penetration-enhancing efficiency and safety. Our research aimed to reveal the penetration-enhancing mechanisms of menthol via a multiscale study. Methods First, the interaction of menthol with the stratum corneum was studied using vertical Franz diffusion cells obtained from the abdominal skin of rats as a model. Then, the skin samples were observed via transmission electron microscopy. Finally, the interaction of different concentrations of menthol with a mixed lipid model of the stratum corneum was investigated via molecular dynamics simulation using the GROMOS 54A7 force field on a microcosmic level. Results At concentrations of 3.5% or lower, menthol changed the original structure of the stratum corneum to varying degrees, which increased its fluidity and facilitated the permeation and storage of menthol. Menthol increased the fluidity of the stratum corneum mainly via two mechanisms. First, menthol had strong hydrogen-bonding capability, and it could compete for the lipid–lipid hydrogen bonding sites, thereby weakening the stability of the hydrogen-bonding network connecting the skin lipids. In addition, menthol had strong affinity for cholesterol, probably due to their similar molecular structures, suggesting that the incorporation of menthol would increase the fluidity of the lipid membrane similarly to cholesterol. Conclusion The penetration-enhancing mechanism of menthol was explained using in vitro and molecular dynamics simulation methods. These findings may advance the basic research of transdermal drug delivery systems and facilitate the discoveries of novel penetration enhancers.

Benchmarking Hybrid Atomistic/Coarse-Grained Schemes for Proteins with an Atomistic Water Layer.

An approach to overcome the limited time and spatial scales in molecular dynamics (MD) simulations is to reduce the number of degrees of freedom in the system through coarse-graining. In hybrid atomistic/coarse-grained (AT/CG) simulations, the region of interest (e.g., the solute) is simulated at a higher level of resolution than the surrounding solvent. Recently, we have reparametrized the interactions between the GROMOS 54A7 force field and the GROMOS CG water model to correctly reproduce solvation free energies of side-chain analogues. In this study, a benchmarking of the AT-CG parametrization using a broad set of 22 proteins is conducted. On the basis of the results, the idea of introducing a thin AT water layer around the solute (protein) is revisited to provide a detailed first solvation shell. Different layer schemes were investigated: (a) the water molecules in the AT water layer around the whole protein were restrained to their respective closest protein atom, and (b) the AT water layer was present only around the charged side chains. Results show that the second scheme is more robust in practice and reduces artifacts from the hybrid model with only a small additional computational cost. In general, this layer scheme was found to preserve the structural properties of the proteins better compared to direct solvation in CG water.

Protein docking using constrained self-adaptive differential evolution algorithm

The objective of protein docking is to achieve a relative orientation and an optimized conformation between two proteins that results in a stable structure with the minimized potential energy. Constrained self-adaptive differential evolution (Cons_SaDE) algorithm is used to find the minimum energy conformation using proposed constraints such as boundary surface complementary interactions, non-bonded inter-atomic allowed distances and finding of interaction and non-interaction sites. With these constraints, Cons_SaDE is efficient enough to explore the promising solutions by gradually self-adapting the strategies and parameters learned from their previous experiences. Modified sampling scheme called rotate only representation is used to represent a docking conformation. GROMOS53A6 force field is used to find the potential energy. To test the performance of this algorithm, few bound and unbound complexes from Protein Data Bank (PDB) and few easy, medium and difficult complexes from Zlab Benchmark 4.0 are used. Buried surface area, root-mean-square deviation (RMSD) and correlation coefficient are some of the metrics applied to evaluate the best docked conformations. RMSD values of the best docked conformations obtained from five popular docking Web servers are compared with Cons_SaDE results, and nonparametric statistical tests for multiple comparisons with control method are implemented to show the performance of this algorithm. Cons_SaDE has produced good-quality solutions for the most of the data sets considered.

The Impact of Using Single Atomistic Long-Range Cutoff Schemes with the GROMOS 54A7 Force Field.

With the recent increase in computing power, the molecular modeling community is now more focused on improving the accuracy and overall quality of biomolecular simulations. For the available simulation packages, force fields, and all other associated methods used, this relates to how well they describe the conformational space and thermodynamic properties of a biomolecular system. The parameter sets of GROMOS force fields have been parametrized and validated with the reaction field (RF) method using charge groups and a twin-range cutoff scheme (0.8/1.4 nm). However, the most recent versions of GROMACS (since v.2016) discontinued the support for charge groups. To take full advantage of the newer and faster versions of this software package with GROMOS 54A7 and RF, we need to evaluate the impact of using a single cutoff scheme (vs twin-range) and of using the Verlet list update method (which is atomistic) compared to the group-based cutoff scheme. Our results show that the GROMOS 54A7 force field seems consistent with a single cutoff, since the resulting conformation and protonation ensembles were indistinguishable. The GROMOS parametrization procedure was also reproduced using an atomistic cutoff scheme, and we have observed that the hydration free energy values of small amino acid side-chain analogues were similar to the ones obtained with the group-based protocol. We do observe a small impact of the atomistic cutoff scheme in the conformational space of the model systems studied (G1-PAMAM and DMPC). However, since the structural properties of these systems are well converged for the cutoff range used (1.4-2.0 nm), unlike with the group-based cutoff schemes, we are confident that the atomistic cutoff can be adopted with RF for MD and constant-pH MD biomolecular simulations using the GROMOS 54A7 force field.

Biomolecular Simulations of Halogen Bonds with a GROMOS Force Field.

Halogen bonds (XBs) are non-covalent interactions in which halogens (X), acting as electrophiles, interact with Lewis bases. XBs are able to mediate protein-ligand recognition and therefore play an important role in rational drug design. In this context, the development of molecular modeling tools that can tackle XBs is paramount. XBs are predominantly explained by the existence of a positive region on the electrostatic potential of X named the σ-hole. Typically, with molecular mechanics force fields, this region is modeled using a charged extra point (EP) linked to X along the R-X covalent bond axis. In this work, we developed the first EP-based strategy for GROMOS force fields (specifically GROMOS 54A7) using bacteriophage T4 lysozyme in complex with both iodobenzene and iodopentafluorobenzene as a prototype system. Several EP parametrization schemes were tested by adding a virtual interaction site to ligand topologies retrieved from the Automated Topology Builder (ATB) and Repository. Contrary to previous approaches using other force fields, our analysis is based on the capability of each parametrization scheme to sample XBs during MD simulations. Our results indicate that the implementation of an EP at a distance from iodine corresponding to Rmin provides a good qualitative description of XBs in MD simulations, supporting the compatibility of our approach with the GROMOS 54A7 force field.

Kinetics and mechanical stability of the fibril state control fibril formation time of polypeptide chains: A computational study.

Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite much progress in the understanding of the protein aggregation process, the factors governing fibril formation rates and fibril stability have not been fully understood. Using lattice models, we have shown that the fibril formation time is controlled by the kinetic stability of the fibril state but not by its energy. Having performed all-atom explicit solvent molecular dynamics simulations with the GROMOS43a1 force field for full-length amyloid beta peptides Aβ40 and Aβ42 and truncated peptides, we demonstrated that kinetic stability can be accessed via mechanical stability in such a way that the higher the mechanical stability or the kinetic stability, the faster the fibril formation. This result opens up a new way for predicting fibril formation rates based on mechanical stability that may be easily estimated by steered molecular dynamics.

Aromatic Rings Commonly Used in Medicinal Chemistry: Force Fields Comparison and Interactions With Water Toward the Design of New Chemical Entities.

The identification of lead compounds usually includes a step of chemical diversity generation. Its rationale may be supported by both qualitative (SAR) and quantitative (QSAR) approaches, offering models of the putative ligand-receptor interactions. In both scenarios, our understanding of which interactions functional groups can perform is mostly based on their chemical nature (such as electronegativity, volume, melting point, lipophilicity etc.) instead of their dynamics in aqueous, biological solutions (solvent accessibility, lifetime of hydrogen bonds, solvent structure etc.). As a consequence, it is challenging to predict from 2D structures which functional groups will be able to perform interactions with the target receptor, at which intensity and relative abundance in the biological environment, all of which will contribute to ligand potency and intrinsic activity. With this in mind, the aim of this work is to assess properties of aromatic rings, commonly used for drug design, in aqueous solution through molecular dynamics simulations in order to characterize their chemical features and infer their impact in complexation dynamics. For this, common aromatic and heteroaromatic rings were selected and received new atomic charge set based on the direction and module of the dipole moment from MP2/6-31G* calculations, while other topological terms were taken from GROMOS53A6 force field. Afterwards, liquid physicochemical properties were simulated for a calibration set composed by nearly 40 molecules and compared to their respective experimental data, in order to validate each topology. Based on the reliance of the employed strategy, we expanded the dataset to more than 100 aromatic rings. Properties in aqueous solution such as solvent accessible surface area, H-bonds availability, H-bonds residence time, and water structure around heteroatoms were calculated for each ring, creating a database of potential interactions, shedding light on features of drugs in biological solutions, on the structural basis for bioisosterism and on the enthalpic/entropic costs for ligand-receptor complexation dynamics.

Role of Counterions in Constant-pH Molecular Dynamics Simulations of PAMAM Dendrimers.

Electrostatic interactions play a pivotal role in the structure and mechanism of action of most biomolecules. There are several conceptually different methods to deal with electrostatics in molecular dynamics simulations. Ionic strength effects are usually introduced using such methodologies and can have a significant impact on the quality of the final conformation space obtained. We have previously shown that full system neutralization can lead to wrong lipidic phases in the 25% PA/PC bilayer (J. Chem. Theory Comput. 2014,10, 5483–5492). In this work, we investigate how two limit approaches to the ionic strength treatment (implicitly with GRF or using full system neutralization with either GRF or PME) can influence the conformational space of the second-generation PAMAM dendrimer. Constant-pH MD simulations were used to map PAMAM’s conformational space at its full pH range (from 2.5 to 12.5). Our simulations clearly captured the coupling between protonation and conformation in PAMAM. Interestingly, the dendrimer conformational distribution was almost independent of the ionic strength treatment methods, which is in contrast to what we have observed in charged lipid bilayers. Overall, our results confirm that both GRF with implicit ionic strength and a fully neutralized system with PME are valid approaches to model charged globular systems, using the GROMOS 54A7 force field.

Effect of mutation on Aβ1-42-Heme complex in aggregation mechanism: Alzheimer’s disease

Amyloid β (Aβ) peptide aggregation is one of the root causes for Alzheimer’s disease. Recently, experimental studies show that three active binding sites (His6, His13 and His14) of Aβ peptides were bound with heme to form Aβ-Heme complex, which leads to inhibit the aggregation process. We apply molecular dynamic simulation to investigate the aggregation pathways of Aβ-Heme peptides. The above three binding sites were mutated by Glycine residue individually and generate three complex systems such as Aβ(His6Gly)-Heme, Aβ(His13Gly)-Heme and Aβ(His14Gly)-Heme. These complexes were simulated in explicit water using gromos53a6 force field for 200ns. We found that the His13Gly mutation increase the β-sheet contents (75%) in Aβ peptide. On the other hand, heme binds with His13 residue of native peptide plays an important role to reduce the formation β-sheet content (50%) in Aβ peptide. This finding is in agreement with experimental study, which showed that the effect of mutation on His6 is not directly involved in β-sheet formation, but the effect of mutation in His13 and His14 has involved in β-sheet formation [J. Neurochem. (2009), 110, 1784–1795]. So, our results may be useful to understand the pathway mechanism of aggregation of Aβ peptides.