CHARMM Force Field Research Articles

Evaluating Coarse-Grained MARTINI Force-Fields for Capturing the Ripple Phase of Lipid Membranes.

Phospholipids, which are an integral component of cell membranes, exhibit a rich variety of lamellar phases modulated by temperature and composition. Molecular dynamics (MD) simulations have greatly enhanced our understanding of phospholipid membranes by capturing experimentally observed phases and phase transitions at molecular resolution. However, the ripple (Pβ') membrane phase, observed as an intermediate phase below the main gel-to-liquid crystalline transition with some lipids, has been challenging to capture with MD simulations, both at all-atom and coarse-grained (CG) resolutions. Here, with an aggregate ∼2.5 μs all-atom and ∼122 μs CGMD simulations, we systematically assess the ability of six CG MARTINI 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid and water force-field (FF) variants, parametrized to capture the DPPC gel and fluid phases, for their ability to capture the Pβ' phase, and compared observations with those from an all-atom FF. Upon cooling from the fluid phase to below the phase transition temperature with smaller (380-lipid) and larger (>2200-lipid) MARTINI and all-atom (CHARMM36 FF) DPPC lipid bilayers, we observed that smaller bilayers with both all-atom and MARTINI FFs sampled interdigitated Pβ' and ripple-like states, respectively. However, while all-atom simulations of the larger DPPC membranes exhibited the formation of the Pβ' phase, MARTINI membranes did not sample interdigitated ripple-like states at larger system sizes. We then demonstrated that the ripple-like states in smaller MARTINI membranes were kinetically trapped structures caused by finite size effects rather than being representative of true Pβ' phases. We showed that a MARTINI FF variant that could capture the tilted Lβ' gel phase, a prerequisite for stabilizing the Pβ' phase, was unable to capture the rippled phase upon cooling. Our study reveals that the current MARTINI FFs (including MARTINI3) may require specific reparametrization of the interaction potentials to stabilize lipid interdigitation, a characteristic of the ripple phase.

Simulations of Diabetic and Non-Diabetic Peripheral Nerve Myelin Lipid Bilayers

The multilayered myelin sheath is a critical component of both central and peripheral nervous systems, forming a protective barrier against axonal damage and facilitating the movement of nervous impulses. It is primarily composed of cholesterol (CHL1), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), sphingomyelin (SM), and galactosylceramide (GalCer) lipids. For rat sciatic nerve myelin (part of the peripheral nervous system, PNS), it has been found that cholesterol and unsaturated fatty acid contents are significantly lower in diabetic than in non-diabetic conditions. In this study, lipid compositions from experimental data are used to create four model rat sciatic nerve myelin lipid bilayers: PI-containing (non-diabetic and diabetic) and PS-containing (non-diabetic and diabetic), which were then simulated using the all-atom CHARMM36 force field. Simulation results of diabetic membranes indicate less rigid, more laterally expansive, and thinner bilayers as well as potentially reduced interactions between GalCer on opposing myelin leaflets, supporting a direct role of the cholesterol content decrease in instigating myelin deterioration and diabetic peripheral neuropathy. Compared to PI-lipids, PS-lipids were found to cause higher inter-lipid spacing and decreased order within membranes as a result of their smaller headgroup size and higher inter-lipid hydrogen bonding potential, which allow them to more frequently reside deeper in the membrane plane and produce pushing effects on other lipids. GalCer deuterium order parameters and non-diabetic headgroup-to-headgroup bilayer thicknesses were compared to experimental data, exhibiting close alignment, supporting the future usage of these models to study the PNS myelin sheath.

Additive CHARMM36 Force Field for Nonstandard Amino Acids.

Nonstandard amino acids are both abundant in nature, where they play a key role in various cellular processes, and can be synthesized in laboratories, for example, for the manufacture of a range of pharmaceutical agents. In this work, we have extended the additive all-atom CHARMM36 and CHARMM General force field (CGenFF) to a large set of 333 nonstandard amino acids. These include both amino acids with nonstandard side chains, such as post-translationally modified and artificial amino acids, as well as amino acids with modified backbone groups, such as chromophores composed of several amino acids. Model compounds representative of the nonstandard amino acids were parametrized for protonation states that are likely at the physiological pH of 7 and, for some more common residues, in both d- and l-stereoisomers. Considering all protonation, tautomeric, and stereoisomeric forms, a total of 406 nonstandard amino acids were parametrized. Emphasis was placed on the quality of both intra- and intermolecular parameters. Partial charges were derived using quantum mechanical (QM) data on model compound dipole moments, electrostatic potentials, and interactions with water. Optimization of all intramolecular parameters, including torsion angle parameters, was performed against information from QM adiabatic potential energy surface (PES) scans. Special emphasis was put on the quality of terms corresponding to PES around rotatable dihedral angles. Validation of the force field was based on molecular dynamics simulations of 20 protein complexes containing different nonstandard amino acids. Overall, the presented parameters will allow for computational studies of a wide range of proteins containing nonstandard amino acids, including natural and artificial residues.

Novel positive allosteric modulator of protease-activated receptor 1 promotes skin wound healing in hairless mice.

Protease-activated receptor 1 (PAR1) is a GPCR expressed in several skin cell types, including keratinocyte and dermal fibroblast. PAR1 activation plays a crucial role in the process of skin wound healing such as thrombosis, inflammation, proliferation and tissue repair. In the present study, we identified a novel positive allosteric modulator of PAR1, GB83, and investigated its effect on skin wound healing. The enhancement of PAR1 activity by GB83 was measured using Fluo-4 calcium assay. In silico docking analysis of GB83 in PAR1 was performed using dock ligands method (CDOCKER) with CHARMm force field. Effects of GB83 on cell viability and gene expression were observed using MTS assay and quantitative real-time PCRs, respectively. SKH-1 hairless mice were used to investigate the wound healing effect of GB83. We demonstrated that GB83 did not activate PAR1 by itself but strongly enhanced PAR1 activation by thrombin and PAR1-activating peptide (AP). In silico docking analysis revealed that GB83 can bind to the PAR1 binding site of vorapaxar. GB83 significantly promoted PAR1-mediated cell viability and migration. In addition, the enhancement of PAR1 activity by GB83 strongly increased gene expression of TGF-β, fibronectin and type I collagen in vitro and promoted skin wound healing in vivo. Our results revealed that GB83 is the first positive allosteric modulator of PAR1 and it can be a useful pharmacological tool for studying PAR1 and a potential therapeutic agent for skin wound healing.

Bridging between material properties of proteins and the underlying molecular interactions.

In this work, we develop a novel method that bridges between material properties of proteins, particularly the modulus of elasticity, and the underlying molecular interactions. To this end, we employ both an all-atom normal mode analysis (NMA) model with the CHARMM force field and an elastic solid model for proteins and protein interfaces. And the "bridge" between the two models is a common physical property predictable by both models: the magnitude of thermal vibrations. This connection allows one to calibrate the Young's moduli of proteins and protein interface regions. We find that the Young's moduli of proteins are in the range of a few Gpa to 10 Gpa, while the Young's moduli of the interface regions are several times smaller. The work is significant as it represents the first attempt to systematically compute the elastic moduli of proteins from molecular interactions.

Molecular insight into the outside‐in activation of integrin αvβ3 by 24( S )‐hydroxycholesterol

Objective Oxysterols such as 25-hydroxycholesterol (25HC) are metabolites of cholesterol produced in the human body. Oxysterols are implicated in many physiological and pathological processes and are shown to regulate the immune system. Recently, we demonstrated that during virus infections, 25HC amplifies proinflammatory response by directly binding to αvβ3 and α5β1 integrins and by activating FAK-NFkB signaling pathway, resulting in the production of proinflammatory mediators such as TNFα and IL-6. Surprisingly, our combined in silico and in vitro studies revealed that 25HC binds to integrins at a novel binding site (site 2) that is distinct from the classical ‘RGD’ binding site, where many extracellular matrix proteins with Arg-Gly-Asp motif are known to bind. Integrins are ubiquitous and play an important role in cell adhesion, cell-cell interactions, cell signaling, and extracellular matrix assembly. Given the abundance of both integrins and endogenous oxysterols, we hypothesized that other oxysterols (other than 25HC) might also activate integrins in a similar fashion. In this study, using a combined computational and experimental approach, we show that 24(S)-hydroxycholesterol (24HC) binds to integrin αvβ3 with high-affinity and triggers proinflammatory response via integrin-FAK pathway. Methods Molecular docking and all-atom molecular dynamics (MD) simulations were used to obtain binding poses and to study the ligand stability and conformational changes, respectively. Induced fit docking of 24HC at site 2 of αVβ3 ectodomain (PDB ID 3IIJE) was performed using MOE software. All-atom MD simulations were performed with GROMACS v5.1.2 using CHARMM36 force field and TIP3P water model. MD simulations were run in triplicates each for 200 ns. The proinflammatory response was determined by the production of TNF using ELISA. Results Our studies reveal the preferred binding orientation of 24HC, which is distinct from that of 25HC. Binding of 24HC induced structural changes in the specificity determining loop (SDL) of the βI domain, leading to an increase in solvent-accessible surface area (SASA) of the RGD site, disruption of native SDL-βI and SDL-β-propeller interface contacts, possibly altering the conformation of the RGD binding site. Robust production of TNF analyzed by ELISA indicates activation of the inflammatory response by 24HC. Similar to 25HC, 24HC also requires integrin-FAK pathway for inflammatory response since, FAK inhibitor, PF-431396 abrogated 24HC mediated response. Conclusions: As the primary cholesterol metabolite with exclusive production in the brain, these findings may provide key insight into factors that influence the complexities of brain function. Our study, for the first time, offers useful insight into the structural and mechanistic bases for the potential proinflammatory response mediated by 24HC through integrins and paves the way for drug discovery efforts towards identifying therapeutics in the treatment of infectious, inflammatory, and immune disorders.

Location and Conformational Ensemble of Menaquinone and Menaquinol, and Protein-Lipid Modulations in Archaeal Membranes.

Halobacteria, a type of archaea in high salt environments, have phytanyl ether phospholipid membranes containing up to 50% menaquinone. It is not understood why a high concentration of menaquinone is required and how it influences membrane properties. In this study, menaquinone-8 headgroup and torsion parameters of isoprenoid tail are optimized in the CHARMM36 force field. Molecular dynamics simulations of archaeal bilayers containing 0 to 50% menaquinone characterize the distribution of menaquinone-8 and menaquinol-8, as well as their effects on mechanical properties and permeability. Menaquinone-8 segregates to the membrane midplane above concentrations of 10%, favoring an extended conformation in a fluid state. Menaquinone-8 increases the bilayer thickness but does not significantly alter the area compressibility modulus and lipid chain ordering. Counterintuitively, menaquinone-8 increases water permeability because it lowers the free energy barrier in the midplane. The thickness increase due to menaquinone-8 may help halobacteria ameliorate hyper-osmotic pressure by increasing the membrane bending constant. Simulations of the archaeal membranes with archaerhodopsin-3 show that the local membrane surface adjusts to accommodate the thick membranes. Overall, this study delineates the biophysical landscape of 50% menaquinone in the archaeal bilayer, demonstrates the mixing of menaquinone and menaquinol, and provides atomistic details about menaquinone configurations.

A theoretical probe into the effects of material and operational variables on water purification with zeolite membranes

Simulation of the effects of Si/Al ratio (material variable) and pressure (operational variable) on water purification with zeolite membranes was discussed. LTA, FAU, and MFI zeolitic structures, respectively having low (1.5), medium (5.6), and high (15) Si/Al ratio were created in Packmol software followed by determining their parameters in LAMMPS varying pressure (12, 24, 36, and 48 MPa). Lenard-Jones interactions were considered applying Tersoff hybrid force field with water modeling based on TIP3P and CHARMM force field. Typical pollutants representing different electronegativity (2.19 for Pb2+ and 1.88 for Co2+) along with chlorine ions (Cl−) were subjected to dynamic simulation for 0.5 ns of equilibrium. Water and ions flux passing the membranes both increase upon pressure rise, particularly at a low Si/Al ratio. Moreover, van der Waals, mean square displacement (MSD), and ion density were captured. Graphical illustrations unveiled dominant mechanisms by VMD software. MFI membrane with rejection above 80% was the bests membrane. The LTA membrane's water flux was the highest, with ca. 3000 ns−1 passing water molecules. van der Waals patterns suggest heavy metal ions trapped in zeolite and their accumulation and agglomeration behind the membrane.

Semi-automated Optimization of the CHARMM36 Lipid Force Field to Include Explicit Treatment of Long-Range Dispersion.

The development of the CHARMM lipid force field (FF) can be traced back to the early 1990s with its current version denoted CHARMM36 (C36). The parametrization of C36 utilized high-level quantum mechanical data and free energy calculations of model compounds before parameters were manually adjusted to yield agreement with experimental properties of lipid bilayers. While such manual fine-tuning of FF parameters is based on intuition and trial-and-error, automated methods can identify beneficial modifications of the parameters via their sensitivities and thereby guide the optimization process. This work introduces a semi-automated approach to reparametrize the CHARMM lipid FF with consistent inclusion of long-range dispersion through the Lennard-Jones particle-mesh Ewald (LJ-PME) approach. The optimization method is based on thermodynamic reweighting with regularization with respect to the C36 set. Two independent optimizations with different topology restrictions are presented. Targets of the optimizations are primarily liquid crystalline phase properties of lipid bilayers and the compression isotherm of monolayers. Pair correlation functions between water and lipid functional groups in aqueous solution are also included to address headgroup hydration. While the physics of the reweighting strategy itself is well-understood, applying it to heterogeneous, complex anisotropic systems poses additional challenges. These were overcome through careful selection of target properties and reweighting settings allowing for the successful incorporation of the explicit treatment of long-range dispersion, and we denote the newly optimized lipid force field as C36/LJ-PME. The current implementation of the optimization protocol will facilitate the future development of the CHARMM and related lipid force fields.

CHARMM36 Lipid Force Field with Explicit Treatment of Long-Range Dispersion: Parametrization and Validation for Phosphatidylethanolamine, Phosphatidylglycerol, and Ether Lipids.

Long-range Lennard-Jones (LJ) interactions have been incorporated into the CHARMM36 (C36) lipid force field (FF) using the LJ particle-mesh Ewald (LJ-PME) method in order to remove the inconsistency of bilayer and monolayer properties arising from the exclusion of long-range dispersion [Yu, Y.; Semi-automated Optimization of the CHARMM36 Lipid Force Field to Include Explicit Treatment of Long-Range Dispersion. J. Chem. Theory Comput. 2021, 10.1021/acs.jctc.0c01326. (preceding article in this issue)]. The new FF is denoted C36/LJ-PME. While the first optimization was based on three phosphatidylcholines (PCs), this work extends the validation and parametrization to more lipids including PC, phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and ether lipids. The agreement with experimental structure data is excellent for PC, PE, and ether lipids. C36/LJ-PME also compares favorably with scattering data of PG bilayers but less so with NMR deuterium order parameters of 1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DMPG) at 303.15 K, indicating a need for future optimization regarding PG-specific parameters. Frequency dependence of NMR T1 spin-lattice relaxation times is well-described by C36/LJ-PME, and the overall agreement with experiment is comparable to C36. Lipid diffusion is slower than C36 due to the added long-range dispersion causing a higher viscosity, although it is still too fast compared to experiment after correction for periodic boundary conditions. When using a 10 Å real-space cutoff, the simulation speed of C36/LJ-PME is roughly equal to C36. While more lipids will be incorporated into the FF in the future, C36/LJ-PME can be readily used for common lipids and extends the capability of the CHARMM FF by supporting monolayers and eliminating the cutoff dependence.

ATP-Magnesium Coordination: Protein Structure-Based Force Field Evaluation and Corrections.

In the numerous molecular recognition and catalytic processes across biochemistry involving adenosine triphosphate (ATP), the common bioactive form is its magnesium chelate, ATP·Mg2+. In aqueous solution, two chelation geometries predominate, distinguished by bidentate and tridentate Mg2+–phosphate coordination. These are approximately isoenergetic but separated by a high energy barrier. Force field-based atomistic simulation studies of this complex require an accurate representation of its structure and energetics. Here we focused on the energetics of ATP·Mg2+ coordination. Applying an enhanced sampling scheme to circumvent prohibitively slow sampling of transitions between coordination modes, we observed striking contradictions between Amber and CHARMM force field descriptions, most prominently in opposing predictions of the favored coordination mode. Through further configurational free energy calculations, conducted against a diverse set of ATP·Mg2+–protein complex structures to supplement otherwise limited experimental data, we quantified systematic biases for each force field. The force field calculations were strongly predictive of experimentally observed coordination modes, enabling additive corrections to the coordination free energy that deliver close agreement with experiment. We reassessed the applicability of the thus corrected force field descriptions of ATP·Mg2+ for biomolecular simulation and observed that, while the CHARMM parameters display an erroneous preference for overextended triphosphate configurations that will affect many common biomolecular simulation applications involving ATP, the force field energy landscapes broadly agree with experimental measurements of solution geometry and the distribution of ATP·Mg2+ structures found in the Protein Data Bank. Our force field evaluation and correction approach, based on maximizing consistency with the large and heterogeneous collection of structural information encoded in the PDB, should be broadly applicable to many other systems.

On the stability of protein–DNA complexes in molecular dynamics simulations using the CUFIX corrections

The molecular dynamics simulation using the so-called force field is a computational method to investigate the conformational stability and dynamics of various biomolecules, including proteins and nucleic acids. While a force-balanced force field is necessary for realistic simulations, recent studies revealed that all standard CHARMM and AMBER force fields over-stabilize the protein–DNA interfaces, resulting in abnormally slow diffusion of DNA-binding proteins. To address this issue, we recently developed the CUFIX corrections by calibrating the electrostatic interactions at the protein–DNA interfaces and demonstrated that the CUFIX corrections dramatically improved the diffusion dynamics of DNA-binding proteins. However, whether the improvement was achieved correctly or at the cost of abnormal destabilization of protein–DNA interactions should be validated. Here, we prove that the CUFIX corrections achieved the balance by demonstrating that the CUFIX corrections maintain the complex structure of DNA and a histone-like protein, Hbb.

Magnesium Coordination of ATP - Force Field Evaluation and Structure-Driven Correction

In the numerous molecular recognition and catalytic processes across biochemistry involving adenosine triphosphate (ATP), the common bioactive form is its magnesium chelate, ATP.Mg2+. In aqueous solution, two chelation geometries predominate, with Mg contacting either the terminal beta and gamma phosphate groups (bidentate) or all three (tridentate). These subforms are approximately isoenergetic, but separated by a high energy barrier. Force field-based atomistic simulation studies of this complex require an accurate representation of its structure and energetics. Here we focused on the energetics of ATP.Mg2+ coordination. With unbiased molecular dynamics simulation showing prohibitively slow interconversion, we devised an enhanced sampling scheme to calculate free energy differences between different Mg2+-phosphate configurations. We observed striking contradictions between Amber and CHARMM force field descriptions, most prominently in opposing predictions of the favoured coordination mode. Through further configurational free energy calculations, conducted against a diverse set of ATP.Mg2+-protein complex structures to supplement otherwise limited experimental data, we observed systematic biases for each force field. However, the force field calculations were strongly predictive of experimentally observed coordination modes, enabling additive corrections to the coordination free energy that deliver close agreement with experiment. Reassessing the applicability of the corrected force field descriptions of ATP.Mg2+ for biomolecular simulation, we observe that calculated properties broadly agree with experimental measurements of solution geometry and the distribution of ATP.Mg2+ structures found in the Protein Data Bank. However, while the corrected Amber force field appears to reproduce both bidentate and tridentate configurations, CHARMM displays an erroneous preference triphosphate overextension. This will affect the interpretation of simulations of bidentate ATP.Mg2+, which comprises the majority of PDB structures.

Bioinorganic Membrane Using A New Kurumi Liquid Crystal

The work characterizes develop a single layer bioinorganic membrane using nano-molecule Kurumi C13H20BeLi2SeSi / C13H19BeLi2SeSi, is well characterize computationally. As its scientific name 3-lithio-3-(6-{3-selena-8-beryllatricyclo [3.2.1.02,⁴]oct-6-en-2-yl}hexyl)-1-sila-2-lithacyclopropane. The work was based on a molecular dynamics (MD) of 1ns, using the CHARMM22 force field, with step 0.001 ps. Calculations indicate that the final structure, arrangement have the tendency to form a single layer micellar structure, when molecular dynamics is performed with a single layer. However, when molecular dynamics were carried out in several layers, indicates the behavior of a liotropic nematic liquid crystal order. Kurumi features the structure polar-apolar-polar predominant. Limitations our study has so far been limited to computational simulation via quantum mechanics e molecular mechanics (QM/MM), an applied theory. Our results and calculations are compatible and with the theory of QM/MM, but their physical experimental verification depend on advanced techniques for their synthesis, obtaining laboratory for experimental biochemical. Going beyond imagination, the most innovative and challenging proposal of the work advances the construction of a structure compatible with the formation of a “new DNA”, based now on the kurumi molecule.

Bioinorganic Membrane Using Kurumi, A New Liquid Crystal

The work characterizes develop a single layer bioinorganic membrane using nano-molecule Kurumi C13H20BeLi2SeSi / C13H19BeLi2SeSi, is well characterize computationally. As its scientific name 3-lithio-3-(6-{3-selena-8-beryllatricyclo [3.2.1.02,⁴] oct-6-en-2-yl}hexyl)-1-sila-2-lithacyclopropane. The work was based on a molecular dynamics (MD) of 1ns, using the CHARMM22 force field, with step 0.001 ps. Calculations indicate that the final structure, arrangement have the tendency to form a single layer micellar structure, when molecular dynamics is performed with a single layer. However, when molecular dynamics were carried out in several layers, indicates the behavior of a liotropic nematic liquid crystal order. Kurumi features the structure polar-apolar-polar predominant. Limitations our study has so far been limited to computational simulation via quantum mechanics e molecular mechanics (QM/MM), an applied theory. Our results and calculations are compatible and with the theory of QM/MM, but their physical experimental verification depend on advanced techniques for their synthesis, obtaining laboratory for experimental biochemical. Going beyond imagination, the most innovative and challenging proposal of the work advances the construction of a structure compatible with the formation of a “new DNA”, based now on the kurumi molecule.

Computational Study of Helical and Helix-Hinge-Helix Conformations of an Anti-Microbial Peptide in Solution by Molecular Dynamics and Vibrational Analysis.

Many classical antimicrobial peptides adopt an amphipathic helical structure at a water-membrane interface. Prior studies led to the hypothesis that a hinge near the middle of a helical peptide plays an important role in facilitating peptide-membrane interactions. Here, dynamics and vibrations of a designed hybrid antimicrobial peptide LM7-2 in solution were simulated to investigate its hinge formation. Molecular dynamics simulation results on the basis of the CHARMM36 force field showed that the α-helix LM7-2 bent around two or three residues near the middle of the peptide, stayed in a helix-hinge-helix conformation for a short period of time, and then returned to a helical conformation. High-resolution computational vibrational techniques were applied on the LM7-2 system when it has α-helical and helix-hinge-helix conformations to understand how this structural change affects its inherent vibrations. These studies concentrated on the calculation of frequencies that correspond to backbone amide bands I, II, and III: vibrational modes that are sensitive to changes in the secondary structure of peptides and proteins. To that end, Fourier transforms were applied to thermal fluctuations in C-N-H angles, C-N bond lengths, and C═O bond lengths of each amide group. In addition, instantaneous all-atom normal mode analysis was applied to monitor and detect the characteristic amide bands of each amide group within LM7-2 during the MD simulation. Computational vibrational results indicate that shapes and frequencies of amide bands II and especially III were altered only for amide groups near the hinge. These methods provide high-resolution vibrational information that can complement spectroscopic vibrational studies. They assist in interpreting spectra of similar systems and suggest a marker for the presence of the helix-hinge-helix motif. Moreover, radial distribution functions indicated an increase in the probability of hydrogen bonding between water and a hydrogen atom connected to nitrogen (HN) in such a hinge. The probability of intramolecular hydrogen bond formation between HN and an amide group oxygen atom within LM7-2 was lower around the hinge. No correlation has been found between the presence of a hinge and hydrogen bonds between amide group oxygen atoms and the hydrogen atoms of water molecules. This result suggests a mechanism for hinge formation wherein hydrogen bonds to oxygen atoms of water replace intramolecular hydrogen bonds as the peptide backbone folds.

CHARMM force field generation for a cationic thiophene oligomer with ffTK.

In the present work, CHARMM force field parameters are generated for a cationic oligomer of N, N, N-trimethyl-3-(4-methylthiophen-3-yl) oxy) propan-1-aminium) which has the potential for sensing biological molecules such as nucleic acids, nucleobases. We have used ffTK (force field tool kit) to obtain potential parameters. MD simulations are performed for 20-mer and its complexes with AMP and ATP. The simulation results are analyzed to see the number of phosphates in adenosine nucleotides effects on the structure of the backbone of oligomer. The UV-VIS calculations for the conformers which possess the most probable radius of gyration are carried out and compared to the experimental ones to validate the generated force field. Graphical Abstract Recent studies have shown that, biologically important anions (ATP, AMP, vb.) change the spectroscopic properties of cationic polythiophenes (CPT) in the solutions. This work aims to generate CHARMM compatible force field parameters for a CPT to explain experimental studies. The type of interactions will be investigated deeply to lead new biosensor studies by examining the formation and the structure of complexes that consist of a oligothiophene and biological molecules, ATP, AMP by molecular dynamic simulations.

Ion Binding Properties and Dynamics of the bcl-2 G-Quadruplex Using a Polarizable Force Field.

G-quadruplexes (GQs) are topologically diverse, highly thermostable noncanonical nucleic acid structures that form in guanine-rich sequences in DNA and RNA. GQs are implicated in transcriptional and translational regulation and genome maintenance, and deleterious alterations to their structures contribute to diseases such as cancer. The expression of the B-cell lymphoma 2 (Bcl-2) antiapoptotic protein, for example, is under transcriptional control of a GQ in the promoter of the bcl-2 gene. Modulation of the bcl-2 GQ by small molecules is of interest for chemotherapeutic development but doing so requires knowledge of the factors driving GQ folding and stabilization. To develop a greater understanding of the electrostatic properties of the bcl-2 promoter GQ, we performed molecular dynamics simulations using the Drude-2017 polarizable force field and compared relevant outcomes to the nonpolarizable CHARMM36 force field. Our simulation outcomes highlight the importance of dipole-dipole interactions in the bcl-2 GQ, particularly during the recruitment of a bulk K+ ion to the solvent-exposed face of the tetrad stem. We also predict and characterize an "electronegative pocket" at the tetrad-long loop junction that induces local backbone conformational change and may induce local conformational changes at cellular concentrations of K+. These outcomes suggest that moieties within the bcl-2 GQ can be targeted by small molecules to modulate bcl-2 GQ stability.

CHARMM-DYES: Parameterization of Fluorescent Dyes for Use with the CHARMM Force Field.

We present CHARMM-compatible force field parameters for a series of fluorescent dyes from the Alexa, Atto, and Cy families, commonly used in Förster resonance energy transfer (FRET) experiments. These dyes are routinely used in experiments to resolve the dynamics of proteins and nucleic acids at the nanoscale. However, little is known about the accuracy of the theoretical approximations used in determining the dynamics from the spectroscopic data. Molecular dynamics simulations can provide valuable insights into these dynamics at an atomistic level, but this requires accurate parameters for the dyes. The complex structure of the dyes and the importance of this in determining their spectroscopic properties mean that parameters generated by analogy to existing parameters do not give meaningful results. Through validation relative to quantum chemical calculation and experiments, the new parameters are shown to significantly outperform those that can be generated automatically, giving better agreement in both the charge distributions and structural properties. These improvements, in particular with regard to orientation of the dipole moments on the dyes, are vital for accurate simulation of FRET processes.

Development of parameters compatible with the CHARMM36 force field for [Fe4S4]2+ clusters and molecular dynamics simulations of adenosine-5’-phosphosulfate reductase in GROMACS 2019

DFT calculations were used to obtain parameters compatible with the CHARMM36 force field for iron-sulfur clusters (Fe-S) of the type [Fe4S4]2+ that are coordinated to dissimilatory adenosine-5’-phosphosulfate reductase (APSrAB). Classical molecular dynamics (MD) simulations were performed on two APSrAB systems to validate the parameters and verify the stability of the studied systems. The time analysis of the parameters inserted into the force field was in reasonable agreement with the experimental X-ray diffraction data. The analysis of the time evolution of the studied systems indicated that these systems and, in particular, the clusters in their respective cavities had a good stability and were in agreement with what was observed in previous works. The parameters obtained provide the basis for the study of APSrAB as well as other systems that contain [Fe4S4]2+ through the CHARMM36 force field.