Combination Of Force Field Research Articles

A Computational Study of Mono- and Poly-Ubiquitin Recognition by the Proteasome Subunit Rpn10

Accurate and timely protein degradation is a vital cellular process. Protein degradation is performed by the 26S proteasome complex, a large multi-subunit molecular machine that recognizes, binds, and degrades protein substrates covalently bound to poly-ubiquitin tags. The 26S proteasome, which recognizes ubiquitin tags through its subunit Rpn10, has a preference for binding K48-linked tetra-ubiquitin chains. However, Rpn10 and its homologs usually have only one or two ubiquitin binding sites, located on their long and flexible C-terminal arms. Here, to examine the role of Rpn10 in the 26S proteasome preference for tetra-ubiquitin tags, we perform molecular dynamics simulations of Rpn10 bound to mono-ubiquitin and poly-ubiquitin chains. To overcome timescale and sampling limitations, we use a combination of a hybrid model force field (PACE) and temperature replica exchange molecular dynamics (T-REMD) simulations. The performed simulations characterize in detail Rpn10 binding to its ubiquitin partners and identify transient contacts that could stabilize Rpn10 (and 26S proteasome) binding to poly-ubiquitin chains. Our results demonstrate at atomic resolution how the flexible Rpn10 subunit contributes to the recognition of poly-ubiquitin tags.

Chemical interaction of water molecules with framework Al in acid zeolites: a periodic ab initio study on H-clinoptilolite.

Periodic quantum-chemistry methods as implemented in the CRYSTAL14 code were considered to analyse the interaction of acid clinoptilolite with water. Initially adsorbed molecules hydrolyse the Al-O bonds, giving rise to defective dealuminated materials. A suitable and representative periodic model of the partially disordered hydrated H-zeolite is the primitive cell (18 T sites) of a decahydrated trialuminated structure of HEU topology. The water distribution inside the material cavities was initially investigated. The model considered for further dealumination was the most stable one from those generated through a combined force field Monte Carlo and ab initio optimization strategy. Optimizations and energy estimations were made at the hybrid DFT level of theory (PBE0 functional) with an atomic basis set of VDZP quality. The energetics of the different pathways involved in the dealumination process was addressed by considering the Gibbs free energy with thermal and zero-point corrections through phonon analysis. It arises that hydrated models exhibit protonated water clusters stabilized by different kinds of H-bonds. The first Al extraction is slightly more energetically favourable from T3 than T2 sites, but at the same time the latter is more probable owing to its larger Al population. However, concerning the second dealumination step, it is more favourable removing the Al atom from both remaining sites after a starting abstraction from T2 rather than T3. These facts determine that the most probable overall pathways go through a first Al removal from T2. The agreement with experimental results is discussed.

Surface Termination of the Metal-Organic Framework HKUST-1: A Theoretical Investigation.

The surface morphology and termination of metal-organic frameworks (MOF) is of critical importance in many applications, but the surface properties of these soft materials are conceptually different from those of other materials like metal or oxide surfaces. Up to now, experimental investigations are scarce and theoretical simulations have focused on the bulk properties. The possible surface structure of the archetypal MOF HKUST-1 is investigated by a first-principles derived force field in combination with DFT calculations of model systems. The computed surface energies correctly predict the [111] surface to be most stable and allow us to obtain an unprecedented atomistic picture of the surface termination. Entropic factors are identified to determine the preferred surface termination and to be the driving force for the MOF growth. On the basis of this, reported strategies like employing "modulators" during the synthesis to tailor the crystal morphology are discussed.

Variation in the structural and optical properties of CdSe/ZnS core/shell nanocrystals with ratios between core and shell radius

The structural and optical properties of CdSe/ZnS core/shell nanocrystals are studied using a combination of valence force field and sp3s⁎ empirical tight-binding model with the aim of studying the relative impacts of ratios (σ) between core and shell radius in the fixed volume. The control and tunability of the strain distribution, single-particle spectra, density of states, overlaps, oscillation strengths, excitonic states and radiative lifetimes by properly engineering structural ratios (σ) are mainly elucidated and quantified. The calculations highlight that the sensitivity of these physical properties with the aspect ratios (σ) is mainly presented. An excellent agreement with literature experiments is achieved from this model. The theoretical results shed light on to the electronic configuration of CdSe/ZnS core/shell nanocrystals and can enable the use of CdSe/ZnS core/shell nanocrystals for further feasible applications.

Probabilistic Determination of Native State Ensembles of Proteins

The motions of biological macromolecules are tightly coupled to their functions. However, while the study of fast motions has become increasingly feasible in recent years, the study of slower, biologically important motions remains difficult. Here, we present a method to construct native state ensembles of proteins by the combination of physical force fields and experimental data through modern statistical methodology. As an example, we use NMR residual dipolar couplings to determine a native state ensemble of the extensively studied third immunoglobulin binding domain of protein G (GB3). The ensemble accurately describes both local and nonlocal backbone fluctuations as judged by its reproduction of complementary experimental data. While it is difficult to assess precise time-scales of the observed motions, our results suggest that it is possible to construct realistic conformational ensembles of biomolecules very efficiently. The approach may allow for a dramatic reduction in the computational as well as experimental resources needed to obtain accurate conformational ensembles of biological macromolecules in a statistically sound manner.

The cost of moving optimally: kinematic path selection.

It is currently unclear whether the brain plans movement kinematics explicitly or whether movement paths arise implicitly through optimization of a cost function that takes into account control and/or dynamic variables. Several cost functions are proposed in the literature that are very different in nature (e.g., control effort, torque change, and jerk), yet each can predict common movement characteristics. We set out to disentangle predictions of the different variables using a combination of modeling and empirical studies. Subjects performed goal-directed arm movements in a force field (FF) in combination with visual perturbations of seen hand position. This FF was designed to have distinct optimal movements for muscle-input and dynamic costs while leaving kinematic cost unchanged. Visual perturbations in turn changed the kinematic cost but left the dynamic and muscle-input costs unchanged. An optimally controlled, physiologically realistic arm model was used to predict movements under the various cost variables. Experimental results were not consistent with a cost function containing any of the control and dynamic costs investigated. Movement patterns of all experimental conditions were adequately predicted by a kinematic cost function comprising both visually and somatosensory perceived jerk. The present study provides clear behavioral evidence that the brain solves kinematic and mechanical redundancy in separate steps: in a first step, movement kinematics are planned; and in a second, separate step, muscle activation patterns are generated.

Atomistic molecular dynamics simulations of CO₂ diffusivity in H₂O for a wide range of temperatures and pressures.

Molecular dynamics simulations were employed for the calculation of diffusion coefficients of CO2 in H2O. Various combinations of existing force fields for H2O (SPC, SPC/E, and TIP4P/2005) and CO2 (EPM2 and TraPPE) were tested over a wide range of temperatures (283.15 K < T < 623.15 K) and pressures (0.1 MPa < P < 100.0 MPa). All force-field combinations qualitatively reproduce the trends of the experimental data; however, two specific combinations were found to be more accurate. In particular, at atmospheric pressure, the TIP4P/2005-EPM2 combination was found to perform better for temperatures lower than 323.15 K, while the SPC/E-TraPPE combination was found to perform better at higher temperatures. The pressure dependence of the diffusion coefficient of CO2 in H2O at constant temperature is shown to be negligible at temperatures lower than 473.15 K, in good agreement with experiments. As temperature increases, the pressure effect becomes substantial. The phenomenon is driven primarily by the higher compressibility of liquid H2O at near-critical conditions. Finally, a simple power-law-type phenomenological equation is proposed to correlate the simulation values; the proposed correlation should be useful for engineering calculations.

Dipeptide Aggregation in Aqueous Solution from Fixed Point-Charge Force Fields.

The description of aggregation processes with molecular dynamics simulations is a playground for testing biomolecular force fields, including a new generation of force fields that explicitly describe electronic polarization. In this work, we study a system consisting of 50 glycyl-l-alanine (Gly-Ala) dipeptides in solution with 1001 water molecules. Neutron diffraction experiments have shown that at this concentration, Gly-Ala aggregates into large clusters. However, general-purpose force fields in combination with established water models can fail to correctly describe this aggregation process, highlighting important deficiencies in how solute–solute and solute–solvent interactions are parametrized in these force fields. We found that even for the fully polarizable AMOEBA force field, the degree of association is considerably underestimated. Instead, a fixed point-charge approach based on the newly developed IPolQ scheme [Cerutti et al. J. Phys. Chem.2013, 117, 2328] allows for the correct modeling of the dipeptide aggregation in aqueous solution. This result should stimulate interest in novel fitting schemes that aim to improve the description of the solvent polarization effect within both explicitly polarizable and fixed point-charge frameworks.

Erratum to Molecular Dynamics Simulations of Highly Crowded Amino Acid Solutions: Comparisons of Eight Different Force Field Combinations with Experiment and with Each Other.

Erratum to Molecular Dynamics Simulations of Highly Crowded Amino Acid Solutions: Comparisons of Eight Different Force Field Combinations with Experiment and with Each Other.

Fast prediction of hydration free energies for SAMPL4 blind test from a classical density functional theory

We report the performance of a classical density functional theory (CDFT) in the competition for the solvation free-energy category of the SAMPL4 blind prediction event. The theoretical calculations were carried out with the TIP3P water model and different combinations of solute configurations and molecular force fields. In comparison with the experimental data, the blind test yields an average unsigned error of 2.38kcal/mol and the root mean square deviation of 2.99kcal/mol. Whereas these numbers are significantly larger than the best results from explicit-solvent MD simulations, we find that the theoretical performance is sensitive to both the molecular force fields and solute configurations and that a comparable level of accuracy can be achieved by a judicious selection of the solute configurations and the force-field parameters. Most importantly, CDFT reduces the computational cost of MD simulation by almost 3 orders of magnitude, making it very attractive for large-scale hydration free-energy calculations (e.g., screening the aqueous solubility of drug-like molecules).

Study on structure-activity relationship of flavonoids’ multidrug resistance-associated protein inhibitory activity

To study the quantitative structure-activity relationship (QSAR) between the stuctures of 29 flavonoids and the inhibitory activity of their multidrug resistance-associated protein (MRP) 1 and 2 by using the comparative molecular similarity index analysis (CoMSIA). By studying the impact of the combination of different molecular force fields, researchers obtained the molecular force fields that played an important role in inhibiting the activity of MRP1 and MRP2, built the optimized QSAR model, and discussed the structural modification method for flavonoids' multidrug resistance-associated protein inhibitor. The results of the study could not only provide the guidance for new drug R&D, but also help partially discuss the synergy mechanism between MRP1 and MRP2 receptors and traditional Chinese medicines containing flavonoids.

How does the electronic continuum model perform in the prediction of the surface tension of salt solutions?

The electronic continuum (EC) model uses a scaling of the charges of the ions in order to model implicitly the polarization into nonpolarizable models. This scaling procedure is applied here to two standard nonpolarizable force fields to investigate the salt concentration dependence of the surface tension and density of NaCl aqueous solutions. The composition of the interface and the orientation of the water molecules at the water surface are reported for different combinations of force fields.

Molecular simulations of physical and chemical adsorption under gas and liquid environments using force field- and quantum mechanics-based methods

Here we review our simulations of adsorption on metal–organic frameworks (MOFs) and platinum (Pt) catalysts, focusing on the modelling methods required to understand these two very different systems. MOFs are porous, crystalline materials with large surface areas, which are promising for a variety of adsorption applications. We review our simulations of gas uptake in PCN-53 (porous coordination network) as well as gas storage in MOFs functionalised with metal alkoxide sites. While fluid–solid interactions in both systems can be modelled quite well using algebraic force fields, the alkoxide sites in the functionalised MOFs require specialised versions, in order to describe the stronger adsorption energies. We discuss grand canonical Monte Carlo (GCMC) simulations of both systems. Pt is a common catalyst, and simulations have proven quite useful for providing molecular level details to understand its functionality. This involves understanding adsorption phenomena, which often requires quantum mechanical calculations. We describe our periodic boundary condition density functional theory (DFT) simulations of Pt-catalysed NO oxidation, focusing on adsorbate geometries and coverage effects. Finally, we describe one of the current ‘grand challenges’ in molecular simulations of adsorption, modelling catalytic activity in aqueous phase, which requires a combination of algebraic force fields, DFT and GCMC.

Predicting adsorption of n-perfluorohexane (n-C6F14) on BCR-704 zeolite using the first principle force field method

Grand Canonical Monte Carlo (GCMC) simulations with ab initio force field were used to predict the adsorption isotherms of n-C6F14 in BCR-704 faujasite (calcium type) zeolite. The force field parameters were derived using the vapor–liquid equilibrium data for the adsorbate molecules, and ab initio data for the adsorbent (zeolite) with argon as a testing particle. The interactions between the adsorbate molecules and the zeolite were represented by using the Lorentz–Berthelot combining rule. Based on a comparison of ab initio and experimental data obtained for methane absorbed on calcium and sodium type zeolites, it was found that the exposed, non-framework calcium cations (Ca2+) must be partially hydroxylated. As the force field parameters were determined using ab initio data, we were able to estimate the percentage of hydroxylation without interference from the force field parameters by using the experimental adsorption data of argon and nitrogen. The hydroxylation ratio of calcium cations was estimated to be 63%. Based on this model and the combined force field parameters, the adsorption isotherm of n-C6F14 on BCR-704 zeolite was predicted and the results are in reasonable agreement with the experimental data.

Molecular Dynamics Simulations of Highly Crowded Amino Acid Solutions: Comparisons of Eight Different Force Field Combinations with Experiment and with Each Other

Although it is now commonly accepted that the highly crowded conditions encountered inside biological cells have the potential to significantly alter the thermodynamic properties of biomolecules, it is not known to what extent the thermodynamics of fundamental types of interactions such as salt bridges and hydrophobic interactions are strengthened or weakened by high biomolecular concentrations. As one way of addressing this question we have performed a series of all-atom explicit solvent molecular dynamics (MD) simulations to investigate the effect of increasing solute concentration on the behavior of four types of zwitterionic amino acids in aqueous solution. We have simulated systems containing glycine, valine, phenylalanine or asparagine at concentrations of 50, 100, 200 and 300 mg/ml. Each molecular system has been simulated for 1 μs in order to obtain statistically converged estimates of thermodynamic parameters, and each has been conducted with 8 different force fields and water models; the combined simulation time is 128 μs. The density, viscosity, and dielectric increments of the four amino acids calculated from the simulations have been compared to corresponding experimental measurements. While all of the force fields perform well at reproducing the density increments, discrepancies for the viscosity and dielectric increments raise questions both about the accuracy of the simulation force fields and, in certain cases, the experimental data. We also observe large differences between the various force fields' descriptions of the interaction thermodynamics of salt bridges and, surprisingly, these differences also lead to qualitatively different predictions of their dependences on solute concentration. For the aliphatic interactions of valine sidechains, fewer differences are observed between the force fields, but significant differences are again observed for aromatic interactions of phenylalanine sidechains. Taken together, the results highlight the potential power of using explicit-solvent simulation methods to understand behavior in concentrated systems but also hint at potential difficulties in using these methods to obtain consistent views of behavior in intracellular environments.

Testing the inter-operability of the CHARMM and SPC/Fw force fields for conformational sampling

One of the challenges in the area of molecular simulation of biointerfaces is to ensure that the interatomic potentials used to describe such interfaces capture the essential chemistry and physics of the system. Here, we report the conformational testing of the inter-operability of the CHARMM and SPC/Fw force fields, the compatibility of which is essential for successful incorporation of a description of biomolecules into current biomineralisation force fields. The effect of the new water model, SPC/Fw, on the conformational equilibrium of two contrasting exemplar tripeptide sequences, RGD and SPT, as described by the CHARMM force field, has been probed by the analysis of results generated from replica-exchange molecular dynamics simulations. We compare the ensemble of conformational states generated from the CHARMM-SPC/Fw force fields with those obtained from the more typical CHARMM-TIPS3P combination. Analysis shows that the findings from the two force field combinations compare very favourably for equilibrium structure determination for both peptides.

Formation of one-dimensional Pt structures in VET-type zeolites: a combined force field and first principles study

The viability of forming stable one-dimensional Pt structures inside the pores of VET-type zeolites is evaluated in this study by using molecular simulations. The resulting nanostructures were optimised and analysed as formed both inside and outside the zeolite. The results show that, theoretically, it is possible to obtain thermally stable ultrathin nanowires in VET zeolites with a low Si/Al ratio using high temperatures during formation. The results also show that the structures obtained with the pcff force field for the ultrathin nanowires are qualitatively similar to those obtained after geometric optimisation with DFT.

Theoretical and experimental study of the pH-dependent interaction of amino acids and MFI-type zeolite

The separation and purification of peptides and proteins using chromatography can make up more than half the amount of the total purification costs of a biotechnological process [1]. The development of cost-efficient processes still suffers from the lack of understanding on a molecular level of adsorption mechanisms of biomolecules on materials surfaces. To explore the power of computer science in supporting experimentally based process development, we applied a combined force field approach with subsequent Density Functional Theory (DFT) calculations. As a first step, we examined the adsorption of the amino acids glycine (gly), l-alanine (ala) and l-lysine (lys) on MFI-type zeolite (MFI). Experimental data from adsorption isotherms and Isothermal Titration Calorimetry (ITC) have proved the adsorption to be strongly pH-dependent. Therefore, we applied the amino acids in their protonated and neutral state in order to simulate low and medium pH values in our computational study. A T33 cluster containing all potential binding regions was used as a model of MFI. Initial geometries for DFT calculations were prepared with force field methods in order to speed up the search in conformational space. Low energy adsorption sites were determined using Adsorption Locator and Forcite modules of Materials Studio 6.0 (Accelrys Inc.). Subsequently, the structures were optimized with DMol3 code (Accelrys Inc.) using the generalized-gradient approximation (GGA) with the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional and the double numerical plus polarization (DNP) basis set. Calculated energies strongly mirror the adsorption affinities derived from experimental adsorption isotherms: (lyslow_pH >> ((ala > gly)low_pH ~ lysmedium_pH)) >> (ala > gly)medium_pH. Furthermore, calculated adsorption energy ratios between protonated amino acids agree very well with the enthalpy ratios derived from low pH ITC experiments: ([ala:gly] = 1.12exp = 1.14calc), ([lys:ala] = 1.72 exp = 1.75 calc), ([lys:gly] = 1.92exp = 1.97calc). Additionally, the adsorption mechanisms of neutral and protonated amino acids were found to be qualitatively different. Neutral amino acids bind via neutral amino group and proton transfer to the active site in zeolite, whereas protonated amino acids bind via carboxyl group. These results illustrate that a judiciously designed combination of atomistic modeling methods can be used as a reliable first step in the design of cost-efficient industrial processes.

Modeling Sorption and Diffusion of Organic Sorbate in Hexadecyltrimethylammonium-Modified Clay Nanopores – A Molecular Dynamics Simulation Study

Organoclays are highly sorptive engineered materials that can be used as amendments in barrier systems or geosynthetic liners. The performance of confining and isolating the nonpolar organic contaminants by those barrier/lining systems is essentially controlled by the process of organic contaminant mass transport in nanopores of organoclays. In this article, we use molecular dynamics (MD) simulations to study the sorption and diffusion of organic sorbates in interlayers of sodium montmorillonite and hexadecyltrimethylammonium (HDTMA(+))-modified montmorillonite clays. Simulated system consisted of the clay framework, interlayer organic cation, water, and organic sorbate. Their interactions were addressed by the combined force field of ClayFF, constant-valence force field, and SPC water model. Simulation results indicated that in HDTMA coated clay nanopores, diffusion of nonpolar species benzene was slowed because they were subjected to influence of both the pore wall and the HDTMA surfactant. This suggested the nonpolar organic compound diffusion in organophilic clays can be affected by molecular size of diffusive species, clay pore size, and organic surfactant loading. Additionally, a model that connected the diffusion rate of organic compounds in the bulk organoclay matrix with macropores and nanopores was established. The impact of intercalated organic cations on the diffusion dominated mass transport of organic compounds yielded insight into the prediction of the apparent diffusion behavior of organic compounds in organic-modified clays.

T-Cell Receptors Binding Orientation over Peptide/MHC Class I Is Driven by Long-Range Interactions

Crystallographic data about T-Cell Receptor – peptide – major histocompatibility complex class I (TCRpMHC) interaction have revealed extremely diverse TCR binding modes triggering antigen recognition. Understanding the molecular basis that governs TCR orientation over pMHC is still a considerable challenge. We present a simplified rigid approach applied on all non-redundant TCRpMHC crystal structures available. The CHARMM force field in combination with the FACTS implicit solvation model is used to study the role of long-distance interactions between the TCR and pMHC. We demonstrate that the sum of the coulomb interactions and the electrostatic solvation energies is sufficient to identify two orientations corresponding to energetic minima at 0° and 180° from the native orientation. Interestingly, these results are shown to be robust upon small structural variations of the TCR such as changes induced by Molecular Dynamics simulations, suggesting that shape complementarity is not required to obtain a reliable signal. Accurate energy minima are also identified by confronting unbound TCR crystal structures to pMHC. Furthermore, we decompose the electrostatic energy into residue contributions to estimate their role in the overall orientation. Results show that most of the driving force leading to the formation of the complex is defined by CDR1,2/MHC interactions. This long-distance contribution appears to be independent from the binding process itself, since it is reliably identified without considering neither short-range energy terms nor CDR induced fit upon binding. Ultimately, we present an attempt to predict the TCR/pMHC binding mode for a TCR structure obtained by homology modeling. The simplicity of the approach and the absence of any fitted parameters make it also easily applicable to other types of macromolecular protein complexes.