CHARMM Force Field Research Articles

Non-equilibrium virus particle dynamics: Microsecond MD simulations of the complete Flock House virus capsid under different conditions

Flock House virus (FHV) is an animal virus and considered a model system for non-enveloped viruses. It has a small, icosahedral capsid (T=3) and a bipartite positive-sense RNA genome. We present an extensive study of the FHV capsid dynamics from all-atom molecular dynamics simulations of the complete capsid. The simulations explore different biologically relevant conditions (neutral/low pH, with/without RNA in the capsid) using the CHARMM force field. The results show that low pH destabilizes the capsid, causing radial expansion, and RNA stabilizes the capsid. The finding of low pH destabilization is biologically relevant because the capsid is exposed to low pH in the endosome, where conformational changes occur leading to genome release. We also observe structural changes at the fivefold and twofold symmetry axes that likely relate to the externalization of membrane active γ peptides through the fivefold vertex and extrusion of RNA at the twofold axis. Simulations using the Amber force field at neutral pH are also performed and display similar characteristics to the CHARMM simulations.

Molecular Dynamics Simulation of Antimicrobial Peptide CM15 in Staphylococcus Aureus and Escherichia coli Model Bilayer Lipid.

In animals and plants, antimicrobial peptides (AMPs) are crucial components of defense mechanisms, as they play a crucial role in innate immunity, which protects hosts from pathogenic bacteria. The CM15 has attracted considerable interest as a novel antibiotic against gram-negative and positive pathogens. The aim of this study was to investigate the permeation potential of the CM15 with membrane bilayers of Staphylococcus aureus and Escherichia coli. The bilayer membranes of Escherichia coli and Staphylococcus aureus were modelled with the resemblance in lipid composition to its biological sample. This study followed Protein-Membrane Interaction (PMI) through successive applications of molecular dynamics simulation by GROMACS and CHARMM36 force field for two sets of 120-ns simulations. Significant results were obtained from analyzing the trajectory of the unsuccessful insertion of CM15 during simulation. Our data suggested that Lysine residues in CM15 and Cardiolipins in membrane leaflets play a crucial role in stability and interaction terms. The obtained results strengthen the insertion possibility through the toroidal model, which should consider for further studies on AMPs interaction.

Structures and Dynamics of DNA Mini-Dumbbells Are Force Field Dependent.

Flexible nucleic acid structures can be challenging to accurately resolve with currently available experimental structural determination techniques. As an alternative, molecular dynamics (MD) simulations can provide a window into understanding the unique dynamics and population distributions of these biomolecules. Previously, molecular dynamics simulations of noncanonical (non-duplex) nucleic acids have proven difficult to accurately model. With a new influx of improved nucleic acid force fields, achieving an in-depth understanding of the dynamics of flexible nucleic acid structures may be achievable. In this project, currently available nucleic acid force fields are evaluated using a flexible yet stable model system: the DNA mini-dumbbell. Prior to MD simulations, nuclear magnetic resonance (NMR) re-refinement was accomplished using improved refinement techniques in explicit solvent to yield DNA mini-dumbbell structures with better agreement between the newly determined PDB snapshots, with the NMR data itself, as well as the unrestrained simulation data. Starting from newly determined structures, a total aggregate of over 800 μs of production data between 2 DNA mini-dumbbell sequences and 8 force fields was collected to compare to these newly refined structures. The force fields tested spanned from traditional Amber force fields: bsc0, bsc1, OL15, and OL21 to Charmm force fields: Charmm36 and the Drude polarizable force field, as well as force fields from independent developers: Tumuc1 and CuFix/NBFix. The results indicated slight variations not only between the different force fields but also between the sequences as well. Given our previous experiences with high populations of potentially anomalous structures in RNA UUCG tetraloops and in various tetranucleotides, we expected the mini-dumbbell system to be challenging to accurately model. Surprisingly, many of the recently developed force fields generated structures in good agreement with experiments. Yet, each of the force fields provided a different distribution of potentially anomalous structures.

Estimation of Hydrazone Derivative Compounds as Anti-Bacterial Agents Against Staphylococcus aureous Through Molecular Docking and Self Consisted Field

Molecular docking is an important computational method for drug design. It can be used to predict the binding interaction of receptor with the ligand. Hydrazone were reported as chemical compounds with =CH-N-NH group. In addition, hydrazone derivative compounds were also reported have various activities, such as antibacterial agents against Staphylococcus aureus. S. aureus is a very serious problem because this bacteria is increasingly resistant to various types of antibiotics (multidrug resistance). S. aureus is also having extraordinary adaptability thus, it can be resistant to many antibiotics. The purpose of this study is to predict whether the hydrazone compounds were active as anti-bacterial agents and also to ensure that the binding interaction is stable before and after docking calculation. Molecular docking research was conducted using the protein target 1N67 (PDB ID), which was derived from the crystallographic structure of hydrazone derivative chemicals. Four hydrazone derivative substances were docked to the protein in this investigation with grid boxes along x, y, and z radii of 67, 86 and 66, respectively. The positive control was chloramphenicol. Self-Consisted Field (SCF) was calculated using AM1 as basis set and molecular dynamic simulation was performed using CHARMM27 force field. The results showed that from 4 tested compounds, only compound 3 with the binding free energy of −6.535 kcal/mol was estimated as active agent against S. aureus. This compound showed very good potential to be an anti-bacterial with the lowest binding free energy value with the highest stability level. HIGHLIGHTS Due to in silico study such as molecular docking, molecular dynamic simulation is an important computational method for drug design. It can be used to predict the binding orientation of small molecule drug candidates to their protein targets. In addition, docking is also can be applied to predict small molecule affinity and activity. Thus, molecular docking has an important role in drug discovery and rational design The ligand interaction with the receptor was more stable due to the decreased binding free energy value The lowest binding free energy and lowest RMSD value of this molecule, which may presumably cause compound 3 to has better binding affinity compare to other compounds GRAPHICAL ABSTRACT

C-B-A Test of DNA Force Fields.

The DNA duplex may be locally strongly bent in complexes with proteins, for example, with polymerases or in a nucleosome. At such bends, the DNA helix is locally in the noncanonical forms A (with a narrow major groove and a large amount of north sugars) or C (with a narrow minor groove and a large share of BII phosphates). To model the formation of such complexes by molecular dynamics methods, the force field is required to reproduce these conformational transitions for a naked DNA. We analyzed the available experimental data on the B-C and B-A transitions under the conditions easily implemented in modeling: in an aqueous NaCl solution. We selected six DNA duplexes which conformations at different salt concentrations are known reliably enough. At low salt concentrations, poly(GC) and poly(A) are in the B-form, classical and slightly shifted to the A-form, respectively. The duplexes ATAT and GGTATACC have a strong and salt concentration dependent bias toward the A-form. The polymers poly(AC) and poly(G) take the C- and A-forms, respectively, at high salt concentrations. The reproduction of the behavior of these oligomers can serve as a test for the balance of interactions between the base stacking and the conformational flexibility of the sugar-phosphate backbone in a DNA force field. We tested the AMBER bsc1 and CHARMM36 force fields and their hybrids, and we failed to reproduce the experiment. In all the force fields, the salt concentration dependence is very weak. The known B-philicity of the AMBER force field proved to result from the B-philicity of its excessively strong base stacking. In the CHARMM force field, the B-form is a result of a fragile balance between the A-philic base stacking (especially for G:C pairs) and the C-philic backbone. Finally, we analyzed some recent simulations of the LacI-, SOX-4-, and Sac7d-DNA complex formation in the framework of the AMBER force field.

Extension of the TraPPE Force Field for Battery Electrolyte Solvents.

Optimizing electrolyte formulations is key to improving performance of Li-/Na-ion batteries, where transport properties (diffusion coefficient, viscosity) and permittivity need to be predicted as functions of temperature, salt concentration and solvent composition. More efficient and reliable simulation models are urgently needed, owing to the high cost of experimental methods and the lack of united-atom molecular dynamics force fields validated for electrolyte solvents. Here the computationally efficient TraPPE united-atom force field is extended to be compatible with carbonate solvents, optimizing the charges and dihedral potential. Computing the properties of electrolyte solvents, ethylene carbonate (EC), propylene carbonate (PC), dimethyl carbonate (DMC), diethyl carbonate (DEC), and dimethoxyethane (DME), we observe that the average absolute errors in the density, self-diffusion coefficient, permittivity, viscosity, and surface tension are approximately 15% of the corresponding experimental values. Results compare favorably to all-atom CHARMM and OPLS-AA force fields, offering computational performance improvement of at least 80%. We further use TraPPE to predict the structure and properties of LiPF6 salt in these solvents and their mixtures. EC and PC form complete solvation shells around Li+ ions, while the salt in DMC forms chain-like structures. In the poorest solvent, DME, LiPF6 forms globular clusters despite DME's higher permittivity than DMC.

Molecular dynamics simulation of phosphatidylcholine membrane in low ionic strengths of sodium chloride

The one-microsecond molecular dynamics simulations of a membrane-protein complex investigate the influence of the aqueous sodium chloride solutions on the structure and dynamics of a palmitoyl-oleoyl-phosphatidylcholine bilayer membrane. The simulations were performed on five different concentrations (40, 150, 200, 300, and 400 mM) in addition to a salt-free system by using the charmm36 force field for all atoms. Four biophysical parameters, (membrane thicknesses of annular and bulk lipids, and the area per lipid of both leaflets), were computed separately. Nevertheless, the area per lipid was expressed by using the Voronoi algorithm. All time-independent analyses were carried out for the last 400 ns trajectories. Different concentrations revealed dissimilar membrane dynamics before equilibration. The biophysical properties of the membrane (thickness, area-per-lipid, and order parameter) have non-significant changes with increasing ionic strength, however, the 150 mM system had exceptional behavior. Sodium cations were dynamically penetrating the membrane forming weak coordinate bonds with single or multiple lipids. Nevertheless, the binding constant was unaffected by the cation concentration. The electrostatic and Van der Waals energies of lipid-lipid interactions were influenced by the ionic strength. On the other hand, the Fast Fourier Transform was performed to figure out the dynamics at the membrane-protein interface. The nonbonding energies of membrane-protein interactions and order parameters explained the differences in the synchronization pattern. All results were consensus with experimental and theoretical works.Communicated by Ramaswamy H. Sarma

A united-atom representation for sphingolipids in the CHARMM force field.

With the development of the CHARMM force field in the 1970s and 1980s came a software package that was able to model the complexity of macromolecules and biomolecular systems. The CHARMM family has since expanded and improved to include such intricacies as cellular membranes. Sphingolipids were originally found in brain extracts and neurons in the late 1800s and have since been found to be common in mammalian plasma membranes. In recent years, these lipids have been included into the CHARMM36; however, there is still more to these lipids that have yet to be implemented in CHARMM. One such inclusion currently being implemented by the authors of this poster is that of a united-atom representation of these sphingolipids. Currently, lipids in CHARMM36 can be modeled using an ‘all-atom’ representation in which all atoms of the lipids are modeled as interaction sites or a ‘united-atom’ representation in which the hydrogens on the lipid tails are combined onto their connected carbons for computational ease. With the recent implementation of a united-atom representation for phospholipids in CHARMM (C36UAr), the authors are working on extending this for sphingolipids. Although an all-atom force field is useful in many cases, a united-atom force field can also be beneficial, such as in modeling large membrane systems where the atomic details of the lipids can be slightly relaxed for computational ease. Thus, the authors’ goal is to create and implement a C36UAr for sphingolipids. The authors hope that this representation will be used by future researchers to study the functions, properties, and applications of cell membranes.

The reconciliation between the experimental and calculated octanol-water partition coefficient of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine using atomistic molecular dynamics: an open question

The octanol-water partition coefficient of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) was investigated using atomistic molecular dynamics simulations via thermodynamic integration and multistate Bennett acceptance ratio methods. The GAFF and CHARMM36 force fields were used with six water models widely used in molecular dynamics simulations. The OPC4 water model provided the best agreement with the experimental octanol-water partition coefficient of DPPC using the two force fields. However, there is still plenty of room for improvement in water models with correct estimation of surface tension that uses better and suitable non-bonded interaction parameters between water-water and water-DPPC. The Gibbs free energy of transferring DPPC from octanol to water phase was calculated to be 19.8 ± 0.3 and 20.2 ± 0.3 kcal mol−1, giving a partition coefficient of 14.5 ± 0.4 and 14.8 ± 0.3 for the GAFF and CHARMM36 force fields, respectively. This study reinforces the importance of developing new water models that reproduce experimental surface tensions to reconcile the water-water and water-DPPC non-bonded interactions and the existing discrepancy between experimental measurements of amphiphilic molecules that are important in many areas of scientific applications and industry such as biophysics, surfactant, colloids, membranes, medicine, nanotechnology, and food and pharmaceutical industries, and so on. It raises two important open questions: Is the experimental octanol-water partition coefficient of DPPC reliable? Or is its calculation accurate using the OPC4 water model? With respect to the experimental measurements, there may be non-treated aspects such as the formation of aggregates in aqueous phase and limit of detection of the applied method. And, in the calculation, some effects are not possible to be considered in a correct way or viable time such as calculating quantum effects, sampling all conformations, considering phase transitions, and correctly evaluating the intermolecular forces to estimate an accurate surface tension. Communicated by Ramaswamy H. Sarma

Xanthatin and 8-epi-xanthatin as new potential colchicine binding site inhibitors: a computational study.

Phytocompounds xanthatin and 8-epi-xanthatin, obtained from Xanthium chinese Mill, showed antitumoral activity in vitro related to the microtubules destabilizing properties of these phytocompounds. Five binding sites for microtubule destabilizing agents have been characterized on tubulin by high-resolution X-ray crystallography: vinca domain, colchicine, pironetin, maytansine site, and more recently, the seventh site. This work aims to develop a comprehensive computational strategy to understand and eventually predict the interaction between xanthatin and 8-epi-xanthatin with the destabilizing-antimitotic binding domain of the tubulin heterodimer. In addition, we propose a putative binding site for these phytocompounds into the microtubule destabilizing binding sites on the tubulin heterodimer. Xanthanolides showed higher stability in the colchicine and pironetin binding sites, whit a greater affinity for the former. In addition, we found that xanthanolides and non-classical colchicine binding site inhibitors share a high structural similarity. The 3D structures for xanthatin and 8-epi-xanthatin were obtained using DFT with the hybrid functional B3LYP and the base 6-31G (d,p), implemented in Gaussian 09. The 3D coordinates for tubulin proteins were downloaded from PDB. The complexes tubulin-xanthanolides were predicted using a Monte-Carlo iterated search combined with the BFGS gradient-based optimizer implemented in the AutoDock Vina. The xanthanolides-tubulin complexes were energy minimized by molecular dynamics simulations at vacuum, and their stabilities were evaluated by solvated molecular dynamics simulations during 100ns. All molecular dynamics simulations were performed using the conjugate gradient method implemented in NAMD2 and CHARMM36 forcefield.

Conformational Search for the Building Block of Proteins Based on the Gradient Gravitational Search Algorithm (ConfGGS) Using Force Fields: CHARMM, AMBER, and OPLS-AA.

Proteins are linear polymers built from a repertoire of 20 different amino acids, which are considered building blocks of proteins. The diversity and versatility of these 20 building blocks with regard to their conformations are key to adopting three-dimensional structures that facilitate proteins to undergo important mechanistic biological processes in living systems. The present investigation reports a conformational search of 20 different amino acids, building blocks of proteins, using three different force fields, CHARMM, AMBER, and OPLS-AA, implemented in the gradient gravitational search algorithm. The search technique (ConfGGS) includes the contribution from both bonded and nonbonded terms using Cartesian coordinates. The efficiency of such conformational searches has also been compared with other optimization algorithms: DE/Best, DE/Rand, and PSO algorithms with respect to computational time and accuracy based on the minimum number of iteration steps and computed lowest mean absolute error (MAE) and mean standard deviation (MSD) values for dihedral angles of respective near-optimal structures. Moreover, the ConfGGS technique has also been extended to an ordered protein fragment (PQITL) extracted from HIV-1 protease (PDB ID: 1YTH), an intrinsically disordered protein fragment, i.e., an amyloid-forming segment (AVVTGVTAV), from the NAC domain of Parkinson's disease protein α-synuclein, residues 69-77 (PDB ID: 4RIK), the experimental NMR atomic-resolution structure of α-synuclein fibrils (PDB ID: 2N0A), and a disulfide bond-containing protein fragment sequence (PCYGWPVCY), residues 59-67 (PDB ID: 6Y4F) toward structure prediction as a close homologue compared with experimental accuracy, using the CHARMM force field. The MolProbity validation results for the protein fragment (PQITL) obtained by ConfGGS/CHARMM are in better agreement with the native protein fragment structure of HIV-1 protease (PDB ID: 1YTH). Furthermore, the computed results have also been compared with the coordinates obtained from the AlphaFold network.

TMAO Destabilizes RNA Secondary Structure via Direct Hydrogen Bond Interactions.

Trimethylamine N-oxide (TMAO) is an osmolyte that accumulates in cells in response to osmotic stress. TMAO stabilizes proteins by the entropic stabilization mechanism, which pictures TMAO as a nanocrowder that predominantly destabilizes the unfolded state. However, the mechanism of action of TMAO on RNA is much less understood. Here, we use all-atom molecular dynamics simulations to investigate how TMAO interacts with a 12-nt RNA hairpin with a high melting temperature, and an 8-nt RNA hairpin, which has a relatively fluid native basin in the absence of TMAO. The use of the two hairpins with different free energy of stabilization allows us to probe the origin of the destabilization effect of TMAO on RNA molecules without the possibility of forming tertiary interactions. We generated multiple trajectories using all-atom molecular dynamics (MD) simulations in explicit water by employing AMBER and CHARMM force fields, both in the absence and presence of TMAO. We observed qualitatively similar RNA-TMAO interaction profiles from the simulations using the two force fields. TMAO hydrogen bond interactions are largely depleted around the paired RNA bases and ribose sugars. In contrast, we show that the oxygen atom in TMAO, the hydrogen bond acceptor, preferentially interacts with the hydrogen bond donors in the solvent exposed bases, such as those in the stem-loop and the destabilized base stacks in the unfolded state, especially in the marginally stable 8-nt RNA hairpin. The predicted destabilization mechanism through TMAO-RNA hydrogen bond interactions could be tested using two-dimensional IR spectroscopy. Since TMAO does not significantly interact with the hydroxyl group of the ribose sugars, we predict that similar results must also hold for DNA.

Molecular Dynamics Simulations of RNA Motifs to Guide the Architectural Parameters and Design Principles of RNA Nanostructures.

Molecular dynamics (MD) simulations can be used to investigate the stability and conformational characteristics of RNA nanostructures. However, MD simulations of an RNA nanostructure is computationally expensive due to the size of nanostructure and the number of atoms. Alternatively, MD simulations of RNA motifs can be used to estimate the conformational stability of constructed RNA nanostructure due to their small sizes. In this chapter, we introduce the preparation and MD simulations of two RNA kissing loop (KL) motifs, a linear KL complex and a bent KL complex, and an RNA nanoring. The initial solvated system and topology files of each system will be prepared by two major force fields, AMBER and CHARMM force fields. MD simulations will be performed by NAMD simulation package, which can accept both force fields. In addition, we will introduce the use of the AMBER cpptraj program and visual molecular dynamics (VMD) for data analysis. We will also discuss how MD simulations of two KL motifs can be used to estimate the conformation and stability of RNA nanoring as well as to explain the vibrational characteristics of RNA nanoring.

Glycosidic α-linked mannopyranose disaccharides: an NMR spectroscopy and molecular dynamics simulation study employing additive and Drude polarizable force fields.

D-Mannose is a structural component in N-linked glycoproteins from viruses and mammals as well as in polysaccharides from fungi and bacteria. Structural components often consist of D-Manp residues joined via α-(1→2)-, α-(1→3)-, α-(1→4)- or α-(1→6)-linkages. As models for these oligo- and polysaccharides, a series of mannose-containing disaccharides have been investigated with respect to conformation and dynamics. Translational diffusion NMR experiments were performed to deduce rotational correlation times for the molecules, 1D 1H,1H-NOESY and 1D 1H,1H-T-ROESY NMR experiments were carried out to obtain inter-residue proton-proton distances and one-dimensional long-range and 2D J-HMBC experiments were acquired to gain information about conformationally dependent heteronuclear coupling constants across glycosidic linkages. To attain further spectroscopic data, the doubly 13C-isotope labeled α-D-[1,2-13C2]Manp-(1→4)-α-D-Manp-OMe was synthesized thereby facilitating conformational analysis based on 13C,13C coupling constants as interpreted by Karplus-type relationships. Molecular dynamics simulations were carried out for the disaccharides with explicit water as solvent using the additive CHARMM36 and Drude polarizable force fields for carbohydrates, where the latter showed broader population distributions. Both simulations sampled conformational space in such a way that inter-glycosidic proton-proton distances were very well described whereas in some cases deviations were observed between calculated conformationally dependent NMR scalar coupling constants and those determined from experiment, with closely similar root-mean-square differences for the two force fields. However, analyses of dipole moments and radial distribution functions with water of the hydroxyl groups indicate differences in the underlying physical forces dictating the wider conformational sampling with the Drude polarizable versus additive C36 force field and indicate the improved utility of the Drude polarizable model in investigating complex carbohydrates.

Structural insights on ionizable Dlin-MC3-DMA lipids in DOPC layers by combining accurate atomistic force fields, molecular dynamics simulations and neutron reflectivity.

Ionizable lipids such as the promising Dlin-MC3-DMA (MC3) are essential for the successful design of lipid nanoparticles (LNPs) as drug delivery agents. Combining molecular dynamics simulations with experimental data, such as neutron reflectivity experiments and other scattering techniques, is essential to provide insights into the internal structure of LNPs, which is not fully understood to date. However, the accuracy of the simulations relies on the choice of force field parameters and high-quality experimental data is indispensable to verify the parametrization. For MC3, different parameterizations in combination with the CHARMM and the Slipids force fields have recently emerged. Here, we complement the existing efforts by providing parameters for cationic and neutral MC3 compatible with the AMBER Lipid17 force field. Subsequently, we carefully assess the accuracy of the different force fields by providing a direct comparison to neutron reflectivity experiments of mixed lipid bilayers consisting of MC3 and DOPC at different pHs. At low pH (cationic MC3) and at high pH (neutral MC3) the newly developed MC3 parameters in combination with AMBER Lipid17 for DOPC give good agreement with the experiments. Overall, the agreement is similar compared to the Park-Im parameters for MC3 in combination with the CHARMM36 force field for DOPC. The Ermilova-Swenson MC3 parameters in combination with the Slipids force field underestimate the bilayer thickness. While the distribution of cationic MC3 is very similar, the different force fields for neutral MC3 reveal distinct differences ranging from strong accumulation in the membrane center (current MC3/AMBER Lipid17 DOPC), over mild accumulation (Park-Im MC3/CHARMM36 DOPC) to surface accumulation (Ermilova-Swenson MC3/Slipids DOPC). These pronounced differences highlight the importance of accurate force field parameters and their experimental validation.

Quantitative Predictions and Experimental Validation of Liquid-Vapor Interfacial Tension in Binary and Ternary Mixtures of Alkanes Using Molecular Dynamics Simulations.

Liquid-vapor interfacial properties of alkane mixtures present a challenge for experimental determination, especially under conditions relevant to the energy industry processes. Molecular dynamics (MD) simulations can accurately predict interfacial tensions (IFTs) for complex alkane mixtures under virtually any conditions, thereby alleviating the need for difficult and costly experiments. MD simulations with the CHARMM force field and empirical corrections for the IFT and pressure were used to obtain the IFT for three binary mixtures of ethane (with n-pentane, n-hexane, and n-nonane) and a ternary system (ethane/n-butane/n-decane) under a variety of conditions. The results were thoroughly validated against experimental data from the literature, and new original IFT data were collected using the pendant drop method. The simulations are able to reproduce the experimental IFT to better than 0.5 mN/m or 5% on average and within 1 mN/m or 10% in the worst case. IFTs for the studied three binary and ternary alkane mixtures were predicted for wide ranges of conditions with no known experimental data. Finally, using the MD simulation data, the reliability of the widely used empirical parachor model for predicting IFT was reaffirmed, and the significance of the empirical parameters examined to establish an optimal balance between the accuracy and broad applicability of the model.

A building-block database of distributed polarizabilities and dipole moments to estimate optical properties of biomacromolecules in isolation or in an explicitly solvated medium.

Since atomic or functional-group properties in the bulk are generally not available from experimental methods, computational approaches based on partitioning schemes have emerged as a rapid yet accurate pathway to estimate the materials behavior from chemically meaningful building blocks. Among several applications, a comprehensive and systematically built database of atomic or group polarizabilities and related opto-electronic quantities would be very useful not only to envisage linear or non-linear optical properties of biomacromolecules but also to improve the accuracy of classical force fields devoted to simulate biochemical processes. In this work, we propose the first entries of such database that contains distributed polarizabilities and dipole moments extracted from fragments of peptides. Twenty three prototypical conformers of the dipeptides alanine-alanine and glycine-glycine were used to extract functional groups such as CH2 , CHCH3 , NH2 , COOH, CONH, thus allowing construction of a diversity of chemically relevant environments. To evaluate the accuracy of our database, reconstructed properties of larger peptides containing up to six residues of alanine and glycine were tested against density functional theory calculations at the M06-HF/aug-cc-pVDZ level of theory. The procedure is particularly accurate for the diagonal components of the polarizability tensor with errors up to 15%. In order to include solvent effects explicitly, the peptides were also surrounded by a box of water molecules whose distribution was optimized using the CHARMM force field. Solvent effects introduced by a classical dipole-dipole interaction model were compared to those obtained from polarizable-continuum model calculations.

Probing Methyl Group Dynamics in Proteins by NMR Cross-Correlated Dipolar Relaxation and Molecular Dynamics Simulations.

Nuclear magnetic resonance (NMR) spin relaxation is the most informative approach to experimentally probe the internal dynamics of proteins on the picosecond to nanosecond time scale. At the same time, molecular dynamics (MD) simulations of biological macromolecules are steadily improving through better physical models, enhanced sampling methods, and increased computational power, and they provide exquisite information about flexibility and its role in protein stability and molecular interactions. Many examples have shown that MD is now adept in probing protein backbone motion, but improvements are still required toward a quantitative description of the dynamics of side chains, for example, probed by the dynamics of methyl groups. Thus far, the comparison of computation with experiment for side chain dynamics has primarily focused on the relaxation of 13C and 2H nuclei induced by autocorrelated variation of spin interactions. However, the cross-correlation of 13C-1H dipolar interactions in methyl groups offers an attractive alternative. Here, we establish a computational framework to extract cross-correlation relaxation parameters of methyl groups in proteins from all-atom MD simulations. To demonstrate the utility of the approach, cross-correlation relaxation rates of ubiquitin are computed from MD simulations performed with the AMBER99SB*-ILDN and CHARMM36 force fields. Simulation results were found to agree well with those obtained by experiment. Moreover, the data obtained with the two force fields are highly consistent.

Branched polyethyleneimine: CHARMM force field and molecular dynamics simulations.

Polyethyleneimine (PEI), one of the non-viral vectors of great interest for gene delivery, was investigated at all-atom level, with particular emphasis on its branched form. We report the extension of our previously published CHARMM force field (FF) for linear PEI, with parameters optimized specifically for branched configurations. A new residue type for the branch connector is introduced and the charges and bonded parameters are derived from ab initio calculations based on a model polymer. The new FF is validated by extensive molecular dynamics simulations of solvated branched PEIs of various protonation fractions and branch lengths. The gyration radii, end-to-end distances, and diffusion coefficients are compared with results for linear PEIs of similar molecular weights and protonation patterns. Solvated complexes of DNA with (linear/branched) PEI were also investigated to determine favorable attachment conformations. The parametrized atomistic force field is suitable for simulations of PEI with arbitrary branching pattern, protonation, and size, and is expected to provide relevant insights regarding optimal conditions for DNA-PEI complex formation.

Simulating Polyproline II-Helix-Rich Peptides with the Latest Kirkwood-Buff Force Field: A Direct Comparison with AMBER and CHARMM.

We simulated the dynamics of a set of peptides characterized by ensembles rich in PPII-helical content, to assess the ability of the most recent Kirkwood-Buff force field (KBFF20) to sample this conformational peculiarity. KBFF has been previously shown to capably reproduce experimental dimensions of disordered proteins, while being limited in confidently sampling structured proteins. Further development of the force field bridged this gap. It is however still unknown what are the main differences between KBFF and AMBER/CHARMM force fields. A direct comparison is now possible as both AMBER/CHARMM force fields have been used to sample peptides rich in PPII-helical content. We found that KBFF20 samples' PPII-helical content qualitatively matches both AMBER and CHARMM force fields, with the main difference being the KBFF ability to populate the αR region of the Ramachandran plot in the set of simulated peptides. Overall, KBFF20 is a well-balanced force field, able to sample the dynamics of both structured and unstructured proteins.