gmak: A Parameter-Space Mapping Strategy for Force-Field Calibration.

In the context of classical molecular simulations, the accuracy of a force field is highly influenced by the values of the relevant simulation parameters. In this work, a parameter-space mapping (PSM) workflow is proposed to aid in the calibration of force-field parameters, based mainly on the following features: (i) regular-grid discretization of the search space; (ii) partial sampling of the search-space grid; (iii) training of surrogate models to predict the estimates of the target properties for nonsampled parameter sets; (iv) interpretation of the results in terms of multiobjective optimization concepts; (v) attenuation of statistical errors achieved via empiric extension of the duration of the simulations; (vi) iterative search-space translation according to a user-defined scalar objective function that measures the accuracy of the force field (e.g.

Comparison of the United- and All-Atom Representations of (Halo)alkanes Based on Two Condensed-Phase Force Fields Optimized against the Same Experimental Data Set.

The level of accuracy that can be achieved by a force field is influenced by choices made in the interaction-function representation and in the relevant simulation parameters. These choices, referred to here as functional-form variants (FFVs), include for example the model resolution, the charge-derivation procedure, the van der Waals combination rules, the cutoff distance, and the treatment of the long-range interactions. Ideally, assessing the effect of a given FFV on the intrinsic accuracy of the force-field representation requires that only the specific FFV is changed and that this change is performed at an optimal level of parametrization, a requirement that may prove extremely challenging to achieve in practice.

Simultaneous parametrization of torsional and third-neighbor interaction terms in force-field development: The LLS-SC algorithm.

The calibration of torsional interaction terms by fitting relative gas-phase conformational energies against their quantum-mechanical values is a common procedure in force-field development. However, much less attention has been paid to the optimization of third-neighbor nonbonded interaction parameters, despite their strong coupling with the torsions. This article introduces an algorithm termed LLS-SC, aimed at simultaneously parametrizing torsional and third-neighbor interaction terms based on relative conformational energies.

Computer Modeling Explains the Structural Reasons for the Difference in Reactivity of Amine Transaminases Regarding Prochiral Methylketones.

Amine transaminases (ATAs) are pyridoxal-5'-phosphate (PLP)-dependent enzymes that catalyze the transfer of an amino group from an amino donor to an aldehyde and/or ketone. In the past decade, the enzymatic reductive amination of prochiral ketones catalyzed by ATAs has attracted the attention of researchers, and more traditional chemical routes were replaced by enzymatic ones in industrial manufacturing. In the present work, the influence of the presence of an α,β-unsaturated system in a methylketone model substrate was investigated, using a set of five wild-type ATAs, the ()-selective from (Atr-TA) and (Mva-TA), the ()-selective from (Cvi-TA), (Rpo-TA), (Vfl-TA) and an engineered variant of (ATA-256 from Codexis).

pyPolyBuilder: Automated Preparation of Molecular Topologies and Initial Configurations for Molecular Dynamics Simulations of Arbitrary Supramolecules.

The construction of a molecular topology file is a prerequisite for any classical molecular dynamics simulation. However, the generation of such a file may be very challenging at times, especially for large supramolecules. While many tools are available to provide topologies for large proteins and other biomolecules, the scientific community researching nonbiological systems is not equally well equipped.

Drug-Loading Capacity of PAMAM Dendrimers Encapsulating Quercetin Molecules: A Molecular Dynamics Study with the 2016H66 Force Field.

The complexation of quercetin molecules with poly(amidoamine) (PAMAM) dendrimers of generation 0-3 was studied by molecular dynamics simulations. Three main points were addressed: (i) the effect of starting from different initial structures; (ii) the performance of the 2016H66 force field (recently validated in the context of dendrimer simulations) in predicting the experimental drug(quercetin)-loading capacity of PAMAM dendrimers; and (iii) the stability of quercetin-PAMAM complexes and their interactions. Initial structures generated by different restraint protocols led to faster convergence compared to initial structures generated by randomly placing the drug molecules in the simulation box.

On the Effect of the Various Assumptions and Approximations used in Molecular Simulations on the Properties of Bio-Molecular Systems: Overview and Perspective on Issues.

Computer simulations of molecular systems enable structure-energy-function relationships of molecular processes to be described at the sub-atomic, atomic, supra-atomic or supra-molecular level and plays an increasingly important role in chemistry, biology and physics. To interpret the results of such simulations appropriately, the degree of uncertainty and potential errors affecting the calculated properties must be considered. Uncertainty and errors arise from (1) assumptions underlying the molecular model, force field and simulation algorithms, (2) approximations implicit in the interatomic interaction function (force field), or when integrating the equations of motion, (3) the chosen values of the parameters that determine the accuracy of the approximations used, and (4) the nature of the system and the property of interest.

Systematic Optimization of a Fragment-Based Force Field against Experimental Pure-Liquid Properties Considering Large Compound Families: Application to Saturated Haloalkanes.

Direct optimization against experimental condensed-phase properties concerning small organic molecules still represents the most reliable way to calibrate the empirical parameters of a force field. However, compared to a corresponding calibration against quantum-mechanical (QM) calculations concerning isolated molecules, this approach is typically very tedious and time-consuming. The present article describes an integrated scheme for the automated refinement of force-field parameters against experimental condensed-phase data, considering entire classes of organic molecules constructed using a fragment library combinatorial isomer enumeration.

Evaluating Classical Force Fields against Experimental Cross-Solvation Free Energies.

Experimental solvation free energies are nowadays commonly included as target properties in the validation and sometimes even in the calibration of condensed-phase force fields. However, this is often done in a nonsystematic fashion, by considering available solvation free energies involving an arbitrary collection of solutes in a limited set of solvents (e.g.

Are all-atom any better than united-atom force fields for the description of liquid properties of alkanes?

Alkanes are a fundamental part in empirical force fields (FF) not only due to their technological relevance, but also due to the prevalence of alkane moieties in organic molecules, e.g., compounds containing a saturated carbon chain.

Predicting the Miscibility and Rigidity of Poly(lactic--glycolic acid)/Polyethylene Glycol Blends via Molecular Dynamics Simulations.

The addition of polyethylene glycol (PEG) chains to poly(lactic--glycolic acid) (PLGA) matrices is extensively used to modulate the biodegradation, drug loading and release, mechanical properties, and chemical stability of the original system. Multiple parameters, including the molecular weight, relative concentration, polarity, and solubility, affect the physicochemical properties of the polymer blend. Here, molecular dynamics simulations with the united-atom 2016H66 force field are used to model the behavior of PLGA and PEG chains and thus predict the overall physicochemical features of the resulting blend.

On the development of a nucleophilic methylthiolation methodology.

Methylthiolation reactions are usually explored to access organosulfur compounds using methanethiol, an extremely flammable and toxic compound. Herein, methylthiomethyl esters were successfully applied as novel methylthiolation reagents in a low cost, transition-metal-free methodology. These reagents allowed the methylthiolation of a wide scope of chalcones, acyl ester derivatives and Morita-Baylis-Hillman acetates with good group tolerance, affording the methylthiolated products in moderate to excellent yields.

gem-Dichlorocyclopropanation of Dicarbonyl Derivatives.

A novel methodology for the 1,1-dichlorocyclopropanation of dicarbonyl conjugated olefins was described. The developed protocol is simple and uses readily accessible starting materials, allowing the isolation of the desired adducts in moderate to excellent yields (up to 99 %). Furthermore, the reaction tolerated scale up to the gram scale; thus highlighting the synthetic potential of this transformation.

Molecular Dynamics Simulations of PAMAM and PPI Dendrimers Using the GROMOS-Compatible 2016H66 Force Field.

A systematic evaluation of the accuracy of the GROMOS-compatible 2016H66 force field in the simulation of dendrimers is performed. More specifically, the poly(amido amine) (PAMAM) and the poly(propyleneimine) (PPI) are considered because of the availability of experimental data and simulation results in the literature. A total of 36 molecular systems are simulated and the radius of gyration, asphericity, density profiles, and the self-diffusion coefficient are monitored in terms of the generation number and pH (low, medium, and high) condition.

Influence of the Treatment of Nonbonded Interactions on the Thermodynamic and Transport Properties of Pure Liquids Calculated Using the 2016H66 Force Field.

The effect of different treatments of the nonbonded interactions in simulations employing the recently introduced GROMOS-compatible 2016H66 force field is evaluated based on calculations carried out with the GROMACS software. This is done considering four thermodynamic and transport properties (pure liquid density, vaporization enthalpy, surface-tension coefficient, and self-diffusion constant) of 58 organic liquids representative of the chemical groups alcohol, ether, aldehyde, ketone, carboxylic acid, ester, amine, amide, thiol, sulfide, disulfide, and aromatic compounds, also including water (SPC model). A dipalmitoylphosphatidylcholine bilayer system is considered as well.

Solvent effects on the decarboxylation of trichloroacetic acid: insights from ab initio molecular dynamics simulations.

The kinetics of trichloroacetic acid (TCA) decarboxylation strongly depends on the solvent in which it occurs, proceeding faster in polar aprotic solvents compared to protic solvents. In particular, the reaction is known to be fast in DMSO even at room temperature and is rather slow in water even at higher temperatures. In order to understand the role of the solvent in the kinetics of TCA decarboxylation, the present study investigates this reaction using both ab initio molecular dynamics (AIMD) simulations in explicit solvents and static electronic structure calculations with the SMD polarizable continuum model, considering DMSO and water as solvents.

New insights into flavivirus biology: the influence of pH over interactions between prM and E proteins.

Diseases caused by flaviviruses, such as dengue and zika, are globally recognized as major threats. During infection, a critical point in their replicative cycle is the maturation step, which occurs throughout the cellular exocytic pathway. This step is a pH-dependent process that involves the modification of the viral envelope by converting prM (pre-membrane) into M (membrane) proteins with the release of a "pr peptide".

New Polymorph Form of Dexamethasone Acetate.

A new monohydrated polymorph of dexamethasone acetate was crystallized and its crystal structure characterized. The different analytical techniques used for describing its structural and vibrational properties were: single crystal and polycrystal X-ray diffraction, solid state nuclear magnetic resonance, infrared spectroscopy. A Hirshfeld surface analysis was carried out through self-arrangement cemented by H-bonds observed in this new polymorph.

Simulating Bilayers of Nonionic Surfactants with the GROMOS-Compatible 2016H66 Force Field.

Polyoxyethylene glycol alkyl ether amphiphiles (CE) are important nonionic surfactants, often used for biophysical and membrane protein studies. In this work, we extensively test the GROMOS-compatible 2016H66 force field in molecular dynamics simulations involving the lamellar phase of a series of CE surfactants, namely CE, CE, CE, CE, and CE. The simulations reproduce qualitatively well the monitored structural properties and their experimental trends along the surfactant series, although some discrepancies remain, in particular in terms of the area per surfactant, the equilibrium phase of CE, and the order parameters of CE, CE, and CE.

Insights into CC Chemokine Ligand 2/Chemokine Receptor 2 Molecular Recognition: A Step Forward toward Antichemotactic Agents.

Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein 1 (MCP-1), is a chemokine that recruits immune cells to inflammatory sites by interacting with G protein-coupled receptor CCR2. The CCL2/CCR2 axis is also involved in pathological processes such as tumor growth and metastasis and hence is currently considered as an important drug target. CCL2 exists in a dynamic monomer-dimer equilibrium that is modulated by CCR2 binding.

The flavivirus capsid protein: Structure, function and perspectives towards drug design.

Flaviviruses, such as dengue and zika viruses, are etiologic agents transmitted to humans mainly by arthropods and are of great epidemiological interest. The flavivirus capsid protein is a structural element required for the viral nucleocapsid assembly that presents the classical function of sheltering the viral genome. After decades of research, many reports have shown its different functionalities and influence over cell normal functioning.

The mechanism by which P250L mutation impairs flavivirus-NS1 dimerization: an investigation based on molecular dynamics simulations.

The flavivirus non-structural protein 1 (NS1) is a conserved glycoprotein with as yet undefined biological function. This protein dimerizes when inside infected cells or associated to cell membranes but also forms lipid-associated hexamers when secreted to the extracellular space. A single amino acid substitution (P250L) is capable of preventing the dimerization of NS1 resulting in lower virulence and slower virus replication.

A GROMOS-Compatible Force Field for Small Organic Molecules in the Condensed Phase: The 2016H66 Parameter Set.

This article reports on the calibration and validation of a new GROMOS-compatible parameter set 2016H66 for small organic molecules in the condensed phase. The calibration is based on 62 organic molecules spanning the chemical functions alcohol, ether, aldehyde, ketone, carboxylic acid, ester, amine, amide, thiol, sulfide, and disulfide, as well as aromatic compounds and nucleic-acid bases. For 57 organic compounds, the calibration targets are the experimental pure-liquid density ρliq and the vaporization enthalpy ΔHvap, as well as the hydration free energy ΔGwat and the solvation free energy ΔGche in cyclohexane, at atmospheric pressure and at (or close to) room temperature.

Association of the anti-tuberculosis drug rifampicin with a PAMAM dendrimer.

The association of the anti-tuberculosis drug rifampicin (RIF) with a 4th-generation poly(amidoamine) (G4-PAMAM) dendrimer was investigated by means of molecular dynamics simulations. The RIF load capacity was estimated to be around 20 RIF per G4-PAMAM at neutral pH. The complex formed by 20 RIF molecules and the dendrimer (RIF20-PAMAM) was subjected to 100 ns molecular dynamics (MD) simulations at two different pH conditions (neutral and acidic).

Long-timescale motions in glycerol-monopalmitate lipid bilayers investigated using molecular dynamics simulation.

The occurrence of long-timescale motions in glycerol-1-monopalmitate (GMP) lipid bilayers is investigated based on previously reported 600 ns molecular dynamics simulations of a 2×8×8 GMP bilayer patch in the temperature range 302-338 K, performed at three different hydration levels, or in the presence of the cosolutes methanol or trehalose at three different concentrations. The types of long-timescale motions considered are: (i) the possible phase transitions; (ii) the precession of the relative collective tilt-angle of the two leaflets in the gel phase; (iii) the trans-gauche isomerization of the dihedral angles within the lipid aliphatic tails; and (iv) the flipping of single lipids across the two leaflets. The results provide a picture of GMP bilayers involving a rich spectrum of events occurring on a wide range of timescales, from the 100-ps range isomerization of single dihedral angles, via the 100-ns range of tilt precession motions, to the multi-μs range of phase transitions and lipid-flipping events.