Effects In Molecular Dynamics Simulations Research Articles

Coarse-grained explicit-solvent molecular dynamics simulations of semidilute unentangled polyelectrolyte solutions.

We present results from explicit-solvent coarse-grained molecular dynamics (MD) simulations of fully charged, salt-free, and unentangled polyelectrolytes in semidilute solutions. The inclusion of a polar solvent in the model allows for a more physical representation of these solutions at concentrations, where the assumptions of a continuum dielectric medium and screened hydrodynamics break down. The collective dynamic structure factor of polyelectrolytes, S(q,t), showed that at [Formula: see text], where [Formula: see text] is the polyelectrolyte peak in the structure factor S(q) and [Formula: see text] is the correlation length, the relaxation time obtained from fits to stretched exponential was [Formula: see text], which describes unscreened Zimm-like dynamics. This is in contrast to implicit-solvent simulations using a Langevin thermostat where [Formula: see text]. At [Formula: see text], a crossover region was observed that eventually transitions to another inflection point [Formula: see text] at length scales larger than [Formula: see text] for both implicit- and explicit-solvent simulations. The simulation results were also compared to scaling predictions for correlation length, [Formula: see text], specific viscosity, [Formula: see text], and diffusion coefficient, [Formula: see text], where [Formula: see text] is the polyelectrolyte concentration. The scaling prediction for [Formula: see text] holds; however, deviations from the predictions for [Formula: see text] and D were observed for systems at higher [Formula: see text], which are in qualitative agreements with recent experimental results. This study highlights the importance of explicit-solvent effects in molecular dynamics simulations, particularly in semidilute solutions, for a better understanding of polyelectrolyte solution behavior.

Molecular Modeling of Water-in-Salt Electrolytes: A Comprehensive Analysis of Polarization Effects and Force Field Parameters in Molecular Dynamics Simulations.

Accurate modeling of highly concentrated aqueous solutions, such as water-in-salt (WiS) electrolytes in battery applications, requires proper consideration of polarization contributions to atomic interactions. Within the force field molecular dynamics (MD) simulations, the atomic polarization can be accounted for at various levels. Nonpolarizable force fields implicitly account for polarization effects by incorporating them into their van der Waals interaction parameters. They can additionally mimic electron polarization within a mean-field approximation through ionic charge scaling. Alternatively, explicit polarization description methods, such as the Drude oscillator model, can be selectively applied to either a subset of polarizable atoms or all polarizable atoms to enhance simulation accuracy. The trade-off between simulation accuracy and computational efficiency highlights the importance of determining an optimal level of accounting for atomic polarization. In this study, we analyze different approaches to include polarization effects in MD simulations of WiS electrolytes, with an example of a Na-OTF solution. These approaches range from a nonpolarizable to a fully polarizable force field. After careful examination of computational costs, simulation stability, and feasibility of controlling the electrolyte properties, we identify an efficient combination of force fields: the Drude polarizable force field for salt ions and non-polarizable models for water. This cost-effective combination is sufficiently flexible to reproduce a broad range of electrolyte properties, while ensuring simulation stability over a relatively wide range of force field parameters. Furthermore, we conduct a thorough evaluation of the influence of various force field parameters on both the simulation results and technical requirements, with the aim of establishing a general framework for force field optimization and facilitating parametrization of similar systems.

Building polarization into protein-inhibitor binding dynamics in rational drug design for rheumatoid arthritis

Standard force field-based simulations to accomplish structure-based evaluations of lead molecules is a powerful tool. Combining protein fragmentation into tractable sub-systems with continuum solvation method is envisaged to enable quantum mechanics-based electronic structure calculations of macromolecules in their realistic environment. This along with incorporation of many-body polarization effect in molecular dynamics simulations may augment an accurate description of electrostatics of protein-inhibitor systems for effective drug design. Rheumatoid arthritis (RA) is a complex autoimmune disorder plagued by the ceiling effect of current targeted therapies, encouraging identification of new druggable targets and corresponding drug design to tackle the refractory form of disease. In this study, polarization-inclusive force field approach has been used to model protein solvation and ligand binding for ‘Mitogen-activated protein kinase’ (MAP3K8), a regulatory node of notable pharmacological relevance in RA synovial biology. For MAP3K8 inhibitors belonging to different scaffold series, the calculations illustrated differential electrostatic contribution to their relative binding affinities and successfully explained examples from available structure-activity relationship studies. Results from this study exemplified i) the advantage of this approach in reliably ranking inhibitors having close nanomolar range activities for the same target; and ii) its prospective application in lead molecule identification aiding drug discovery efforts in RA. Communicated by Ramaswamy H. Sarma

Investigating finite-size effects in molecular dynamics simulations of ion diffusion, heat transport, and thermal motion in superionic materials.

The effects of the finite size of the simulation box in equilibrium molecular dynamics simulations are investigated for prototypical superionic conductors of different types, namely, the fluorite-structure materials PbF2, CaF2, and UO2 (type II), and the α phase of AgI (type I). Largely validated empirical force-fields are employed to run ns-long simulations and extract general trends for several properties, at increasing size and in a wide temperature range. This work shows that, for the considered type-II superionic conductors, the diffusivity dramatically depends on the system size and that the superionic regime is shifted to larger temperatures in smaller cells. Furthermore, only simulations of several hundred atoms are able to capture the experimentally observed, characteristic change in the activation energy of the diffusion process, occurring at the order-disorder transition to the superionic regime. Finite-size effects on ion diffusion are instead much weaker in α-AgI. The thermal conductivity is found generally smaller for smaller cells, where the temperature-independent (Allen-Feldman) regime is also reached at significantly lower temperatures. The finite-size effects on the thermal motion of the non-mobile ions composing the solid matrix follow the simple law that holds for solids.

Casimir force and its effects on pull-in instability modelled using molecular dynamics simulations.

We present a new methodology to incorporate the Casimir forces within the molecular dynamics (MD) framework. At atomistic scales, the potential energy between two particles arising due to the Casimir effect can be represented as U(r ij ) = C/r 7. Incorporating the Casimir effect in MD simulations requires the knowledge of C, a problem hitherto unsolved. We overcome this by equating the total potential energy contributions due to each atomistic pair with the potential energy of continuum scale interacting bodies having similar geometries. After having identified the functional form of C, standard MD simulations are augmented with the potential energy contribution due to pairwise Casimir interactions. The developed framework is used to study effects of the Casimir force on the pull-in instability of rectangular and hollow cylindrical shaped deformable electrodes separated by a small distance from a fixed substrate electrode. Our MD results for pull-instability qualitatively agree with the previously reported analytical results but are quantitatively different. The effect of using longer-ranged Casimir forces in a constant temperature environment on the pull-in behaviour has also been studied.

Connection between sliding friction and phonon lifetimes: Thermostat-induced thermolubricity effects in molecular dynamics simulations

A typical nanotribology simulation setup is the semi-infinite substrate, featuring a sliding bead on top, and with the lower substrate layers thermostatted to control temperature. A challenge is dealing with phonons that backreflect from the substrate lower boundary, as these will artificially reduce the friction FR acting on the sliding bead. One proposed solution is to use a Langevin thermostat, operating at temperature TLAN, and with the corresponding damping parameter, GAMMA, optimally tuned such that FR is maximized [Benassi etal, PHYSREVB, V82, P081401, 2010]. In this paper, the method is revisited, and related to the substrate phonon lifetime, the substrate temperature TSUB, and the sliding speed. At low sliding speed, where the time between stick-slip events is large compared to the phonon lifetime, we do not observe much dependence of FR on GAMMA, and here thermostat tuning is not required. At high sliding speed, upon varying GAMMA, we confirm the aforementioned friction maximum, but also observe a pronounced minimum in TSUB, which here deviates from TLAN. For substrate particle interactions that are strongly anharmonic, the variation of FR with GAMMA can be understood as a manifestation of thermolubricity, backreflections being essentially unimportant. In contrast, for harmonic interactions, where phonon lifetimes become very long, FR is strongly affected by backreflecting phonons, though not enough to overturn thermolubricity.

Density artefacts at interfaces caused by multiple time-step effects in molecular dynamics simulations.

Background:Molecular dynamics (MD) simulations have become an important tool to provide insight into molecular processes involving biomolecules such as proteins, DNA, carbohydrates and membranes. As these processes cover a wide range of time scales, multiple time-step integration methods are often employed to increase the speed of MD simulations. For example, in the twin-range (TR) scheme, the nonbonded forces within the long-range cutoff are split into a short-range contribution updated every time step (inner time step) and a less frequently updated mid-range contribution (outer time step). The presence of different time steps can, however, cause numerical artefacts. Methods:The effects of multiple time-step algorithms at interfaces between polar and apolar media are investigated with MD simulations. Such interfaces occur with biological membranes or proteins in solution. Results:In this work, it is shown that the TR splitting of the nonbonded forces leads to artificial density increases at interfaces for weak coupling and Nosé-Hoover (chain) thermostats. It is further shown that integration with an impulse-wise reversible reference system propagation algorithm (RESPA) only shifts the occurrence of density artefacts towards larger outer time steps. Using a single-range (SR) treatment of the nonbonded interactions or a stochastic dynamics thermostat, on the other hand, resolves the density issue for pairlist-update periods of up to 40 fs. Conclusion:TR schemes are not advisable to use in combination with weak coupling or Nosé-Hoover (chain) thermostats due to the occurrence of significant numerical artifacts at interfaces.

Density artefacts at interfaces caused by multiple time-step effects in molecular dynamics simulations.

Background:Molecular dynamics (MD) simulations have become an important tool to provide insight into molecular processes involving biomolecules such as proteins, DNA, carbohydrates and membranes. As these processes cover a wide range of time scales, multiple time-step integration methods are often employed to increase the speed of MD simulations. For example, in the twin-range (TR) scheme, the nonbonded forces within the long-range cutoff are split into a short-range contribution updated every time step (inner time step) and a less frequently updated mid-range contribution (outer time step). The presence of different time steps can, however, cause numerical artefacts. Methods:The effects of multiple time-step algorithms at interfaces between polar and apolar media are investigated with MD simulations. Such interfaces occur with biological membranes or proteins in solution. Results:In this work, it is shown that the TR splitting of the nonbonded forces leads to artificial density increases at interfaces for weak coupling and Nosé-Hoover (chain) thermostats. It is further shown that integration with an impulse-wise reversible reference system propagation algorithm (RESPA) only shifts the occurrence of density artefacts towards larger outer time steps. Using a single-range (SR) treatment of the nonbonded interactions or a stochastic dynamics thermostat, on the other hand, resolves the density issue for pairlist-update periods of up to 40 fs. Conclusion:TR schemes are not advisable to use in combination with weak coupling or Nosé-Hoover (chain) thermostats due to the occurrence of significant numerical artifacts at interfaces.

Density artefacts at interfaces caused by multiple time-step effects in molecular dynamics simulations

Background: Molecular dynamics (MD) simulations have become an important tool to provide insight into molecular processes involving biomolecules such as proteins, DNA, carbohydrates and membranes. As these processes cover a wide range of time scales, multiple time-step integration methods are often employed to increase the speed of MD simulations. For example, in the twin-range (TR) scheme, the nonbonded forces within the long-range cutoff are split into a short-range contribution updated every time step (inner time step) and a less frequently updated mid-range contribution (outer time step). The presence of different time steps can, however, cause numerical artefacts. Methods: The effects of multiple time-step algorithms at interfaces between polar and apolar media are investigated with MD simulations. Such interfaces occur with biological membranes or proteins in solution. Results: In this work, it is shown that the TR splitting of the nonbonded forces leads to artificial density increases at interfaces for weak coupling and Nosé-Hoover (chain) thermostats. It is further shown that integration with an impulse-wise reversible reference system propagation algorithm (RESPA) only shifts the occurrence of density artefacts towards larger outer time steps. Using a single-range (SR) treatment of the nonbonded interactions or a stochastic dynamics thermostat, on the other hand, resolves the density issue for pairlist-update periods of up to 40 fs. Conclusion: TR schemes are not advisable to use in combination with weak coupling or Nosé-Hoover (chain) thermostats due to the occurrence of significant numerical artifacts at interfaces.

Nuclear quantum effects in molecular dynamics simulations

To take into account nuclear quantum effects on the dynamics of atoms, the path integral molecular dynamics (PIMD) method used since 1980s is based on the formalism developed by R. P. Feynman. However, the huge computation time required for the PIMD reduces its range of applicability. Another drawback is the requirement of additional techniques to access time correlation functions (ring polymer MD or centroid MD). We developed an alternative technique based on a quantum thermal bath (QTB) which reduces the computation time by a factor of ∼20. The QTB approach consists in a classical Langevin dynamics in which the white noise random force is replaced by a Gaussian random force having the power spectral density given by the quantum fluctuation-dissipation theorem. The method has yielded satisfactory results for weakly anharmonic systems: the quantum harmonic oscillator, the heat capacity of a MgO crystal, and isotope effects in 7LiH and 7LiD. Unfortunately, the QTB is subject to the problem of zero-point energy leakage (ZPEL) in highly anharmonic systems, which is inherent in the use of classical mechanics. Indeed, a part of the energy of the high-frequency modes is transferred to the low-frequency modes leading to a wrong energy distribution. We have shown that in order to reduce or even eliminate ZPEL, it is sufficient to increase the value of the frictional coefficient. Another way to solve the ZPEL problem is to combine the QTB and PIMD techniques. It requires the modification of the power spectral density of the random force within the QTB. This combination can also be seen as a way to speed up the PIMD.

Density artefacts at interfaces caused by multiple time-step effects in molecular dynamics simulations

Background:Molecular dynamics (MD) simulations have become an important tool to provide insight into molecular processes involving biomolecules such as proteins, DNA, carbohydrates and membranes. As these processes cover a wide range of time scales, multiple time-step integration methods are often employed to increase the speed of MD simulations. For example, in the twin-range (TR) scheme, the nonbonded forces within the long-range cutoff are split into a short-range contribution updated every time step (inner time step) and a less frequently updated mid-range contribution (outer time step). The presence of different time steps can, however, cause numerical artefacts.Methods:The effects of multiple time-step algorithms at interfaces between polar and apolar media are investigated with MD simulations. Such interfaces occur with biological membranes or proteins in solution.Results:In this work, it is shown that the TR splitting of the nonbonded forces leads to artificial density increases at interfaces. The presence of the observed artefacts was found to be independent of the interface shape and the thermostatting method used. It is further shown that integration with an impulse-wise reversible reference system propagation algorithm (RESPA) only shifts the occurrence of density artefacts towards larger outer time steps. Using a single-range (SR) treatment of the nonbonded interactions, on the other hand, resolves the density issue for pairlist-update periods of up to 40 fs.Conclusion:A SR scheme avoids numerical artefacts and offers an interesting alternative to TR RESPA with respect to performance optimization.

(Invited) In Situ Accurate Analysis of Colloidal Nanoparticles via Four Wave Mixing

Four-wave mixing (FWM) is used to measure the vibrational modes of nanoparticles in solution. The vibrations give information about the particle size, material properties and shape. This method has been used for in-situ monitoring of the growth of nanoparticles with high accuracy, as confirmed by electron microscopy analysis. We observe a threshold in the FWM signal which we believe is from a cavity forming around the nanoparticles that reduces viscous damping. We have observed this effect in molecular dynamics simulations as well. Here we report a highly accurate method for the analysis of colloidal nanoparticles by means of four wave mixing (FWM). Other optical methods exist to analyse nanoparticles in solution, such as extinction and dynamic light scattering. Extinction is widely used in plasmonic nanoparticle analysis; however, it is not very sensitive to particle size, even though it is quite sensitive to particle shape. For accurate sizing and shape characterization, usually transmission electron microscopy is used as an alternative measure. Previously we developed an optical tweezer method to measure individual nanoparticles, including proteins and DNA [1,2]. This method interfered two lasers at the trapping site to create a beat signal with high frequency that excited the vibration modes of the trapped nanoparticle. The vibration resonance was measured indirectly via increased motion of the trapped nanoparticle. We developed the FWM technique to analyse many nanoparticles in solution, instead of individually. In FWM, two laser beams are interfered with a slight frequency difference (in the 10 GHz – 10 THz range). The setup is based on an early degenerate FWM configuration [3]. This drives oscillations in the nanoparticles via electrostriction. When the oscillation frequency matches a natural vibration resonance of the nanoparticles, extremely strong FWM is observed by scattering of a third beam off of a dynamic grating induced by the electrostriction force. The vibration resonances allow for accurate sizing and size distribution information. For example, 2 nm gold nanoparticles give a resonance at 1.5 THz. The resonance frequencies allow for precise determination of nanoparticle size and shape, as has been verified by electron microscopy measurements. We have also demonstrated that this method can be used for in-situ growth characterization of nanoparticles [4]. Furthermore, complex shaped materials (nanoprisms, octahedrons, nanorods) can be analysed with this technique, giving insight into their size and shape [5, 6]. The observed four wave mixing signal is extremely strong and it shows a turn-on threshold [7, 8]. We have ruled out a stimulated threshold here, and so we believe that this strong response is really the result of a sudden reduction in damping from the water environment, akin to cavitation. We have used molecular dynamics simulations to test this hypothesis, and found that they also produce a threshold. In conclusion, we have demonstrated a method for characterizing nanoparticles in situ via electrostriction. This approach is highly accurate and may be used as an alternative to electron microscopy, dynamic light scattering and extinction measurements. We are also intrigued at the cavitation effect that allows for such a strong signal even with weakly focussed continuous wave diode lasers and we believe this effect will allow for a new class of strong nonlinear optical materials. S. Wheaton, R. M. Gelfand, R. Gordon, Nature Photonics 9, 68-72 (2015).A. Kotnala, S. Wheaton, R. Gordon, Nanoscale 7, 2295-2300 (2015).P. W. Smith, A. Ashkin, W. J. Tomlinson, Optics Letters 6 284-286 (1981). J. Wu, D. Xiang, R. Gordon, Analytical Chemistry 89, 2196-2200 (2017). J. Wu, D. Xiang, G. Hajisalem, F.C. Lin, J.S. Huang, R. Gordon, Optics Express 24, 23747-23754 (2016).J. Wu, D. Xiang, R. Gordon, Optics Express 24, 12458-12465 (2016).D. Xiang, J. Wu, J. Rottler, R. Gordon, Nano Letters 16, 3638-3641(2016).D. Xiang, R. Gordon, ACS Photonics 3, 1421-1425 (2016).

Entangled trajectories Hamiltonian dynamics for treating quantum nuclear effects.

A simple and robust methodology, dubbed Entangled Trajectories Hamiltonian Dynamics (ETHD), is developed to capture quantum nuclear effects such as tunneling and zero-point energy through the coupling of multiple classical trajectories. The approach reformulates the classically mapped second-order Quantized Hamiltonian Dynamics (QHD-2) in terms of coupled classical trajectories. The method partially enforces the uncertainty principle and facilitates tunneling. The applicability of the method is demonstrated by studying the dynamics in symmetric double well and cubic metastable state potentials. The methodology is validated using exact quantum simulations and is compared to QHD-2. We illustrate its relationship to the rigorous Bohmian quantum potential approach, from which ETHD can be derived. Our simulations show a remarkable agreement of the ETHD calculation with the quantum results, suggesting that ETHD may be a simple and inexpensive way of including quantum nuclear effects in molecular dynamics simulations.

In Situ Accurate Analysis of Colloidal Nanoparticles via Four Wave Mixing

ABSTRACTFour-wave mixing (FWM) is used to measure the vibrational modes of nanoparticles in solution. The vibrations give information about the particle size, material properties and shape. This method has been used for in-situ monitoring of the growth of nanoparticles with high accuracy, as confirmed by electron microscopy analysis. We observe a threshold in the FWM signal which we believe is from a cavity forming around the nanoparticles that reduces viscous damping. We have observed this effect in molecular dynamics simulations as well.

Inclusion of ph Effects in Molecular Dynamics Simulations of Membranes and Membrane Proteins

Standard molecular simulation methods based on classical force fields typically assume only a fixed protonation state of systems. This assumption generally only permits a limited treatment of pH effects, for example, consideration of extreme acidic/basic conditions or situations where a small number of protonation states can be explicitly enumerated. Importantly, the standard approach cannot be scaled to chemical systems with a large number of titrateable sites such as lipid head groups or assemblies of protein subunits. Here we describe the development and application of a scalable and extensible method for including pH effects in molecular dynamics simulations. In contrast to other constant pH methods, the new method, based on a hybrid of non-equilibrium molecular dynamics and Monte Carlo, can be easily scaled to handle large heterogeneous systems, i.e., not only globular proteins. We present a validation of the method and its implementation in the program NAMD. Finally, we also present proof of concept studies on large biomolecular membrane systems.

Experimental and Modeling Studies of an Unusual Water-Filled Pore Structure with Possible Mechanistic Implications in Family 48 Cellulases

Molecular dynamics simulations were used to study the possible catalytic role of an unusual conserved water-filled pore structure in the family 48 cellulase enzyme Cel48A from Thermobifida fusca. It was hypothesized that this pore serves as the pathway for the water molecules consumed in the hydrolysis catalyzed by the enzyme to reach the active site in a continuous stream to participate in the processive reactions. Theoretical mutants of this enzyme were created in which all of the residues lining the pore were made hydrophobic, which had the effect in molecular dynamics simulations of emptying the pore of water molecules and preventing any from passing through the pore on the simulation time scale. Mutants with smaller numbers of substitutions of this nature, which could be created experimentally by site-directed mutagenesis, were also identified from simulations, and these proteins were subsequently produced in Escherichia coli, expressed and purified, but were found to not fold in a manner similar to the wild type protein, preventing the determination of the importance of the water pore for activity. It is possible that the presence of a small vacuum in the pore was responsible for the instability of the mutants. In addition, alternate pathways were observed in the simulations that would allow water molecules to reach the active site of the enzyme, suggesting that the hypothesis that the pore has functional significance might be incorrect.

Polarizability effects in molecular dynamics simulations of the graphene-water interface

The importance of including the polarizability of both water and graphene in molecular dynamics simulations of the water/graphene system was quantified. A thin film of either rigid single point charge extended (SPC/E) water or polarizable simple 4-site water model with Drude polarizability (SWM4_DP) water on non-polarizable and polarizable graphene surfaces was simulated. The graphene surface was either maintained neutral or charged, positively and negatively. The results suggest that SPC∕E and SWM4_DP water models yield very similar predictions for the water structural properties on neutral non-polarizable graphene, although they yield slightly different dynamical properties of interfacial water on neutral non-polarizable graphene. More pronounced were the differences obtained when graphene was modeled with a polarizable force field. In particular, the polarizability of graphene was found to enhance the number of interfacial SWM4_DP water molecules pointing one of their OH bonds towards the neutral surface. Despite this structural difference, the dynamical properties predicted for the interfacial SWM4_DP water were found to be independent on polarizability as long as the polarizability of a carbon atom is smaller than α = 0.878 A. On charged graphene surfaces, the effect of polarizability of graphene on structural properties and some dynamical properties of SWM4_DP water is negligible because electrostatic forces due to surface charge dominate polarization forces, as expected. For all cases, our results suggest that the hydrogen bond network is insensitive to the polarizability of both water and graphene. Understanding how these effects will determine the accumulation of ions near neutral or charged graphene could have important implications for applications in the fields of energy storage and water desalination.

Computing Wigner distributions and time correlation functions using the quantum thermal bath method: application to proton transfer spectroscopy

Langevin dynamics coupled to a quantum thermal bath (QTB) allows for the inclusion of vibrational quantum effects in molecular dynamics simulations at virtually no additional computer cost. We investigate here the ability of the QTB method to reproduce the quantum Wigner distribution of a variety of model potentials, designed to assess the performances and limits of the method. We further compute the infrared spectrum of a multidimensional model of proton transfer in the gas phase and in solution, using classical trajectories sampled initially from the Wigner distribution. It is shown that for this type of system involving large anharmonicities and strong nonlinear coupling to the environment, the quantum thermal bath is able to sample the Wigner distribution satisfactorily and to account for both zero point energy and tunneling effects. It leads to quantum time correlation functions having the correct short-time behavior, and the correct associated spectral frequencies, but that are slightly too overdamped. This is attributed to the classical propagation approximation rather than the generation of the quantized initial conditions themselves.

Macroscopic nucleation phenomena in continuum media with long-range interactions

Nucleation, commonly associated with discontinuous transformations between metastable and stable phases, is crucial in fields as diverse as atmospheric science and nanoscale electronics. Traditionally, it is considered a microscopic process (at most nano-meter), implying the formation of a microscopic nucleus of the stable phase. Here we show for the first time, that considering long-range interactions mediated by elastic distortions, nucleation can be a macroscopic process, with the size of the critical nucleus proportional to the total system size. This provides a new concept of “macroscopic barrier-crossing nucleation”. We demonstrate the effect in molecular dynamics simulations of a model spin-crossover system with two molecular states of different sizes, causing elastic distortions.

Molecular Dynamics Studies of Human β-Glucuronidase

Problem statement: The enzyme β-glucuronidase is being used as a reporter molecule in the area of genetic engineering, as a component of prodrug therapy in cancer treatment and in the scouring process of cotton fabrics. However, a detailed understanding of the factors responsible for the stability and the activity of this enzyme is still not available. Molecular Dynamics (MD) simulations provide an estimate of equilibrium and dynamic properties of enzyme systems that cannot be calculated analytically. With this perspective, molecular dynamics simulations of human β-glucuronidase (GUS) have been carried out to determine the behavior of this enzyme in vacuum and solvent environments at a defined temperature. Approach: CHARMM force field along with distance dependent dielectric model was used to represent the solvent environment in the MD simulations. The parameters employed in various stages of MD simulations had been selected based on repeated trials under various conditions as a method of choosing the optimum parameters for each stage. Results: It was found that simulations in vacuum caused the backbone of GUS to have smaller fluctuations from their mean values compared with the fluctuation in implicit solvent simulations, due to the fact that vacuum environment did not provide for the electrostatic interactions affecting the backbone of GUS that may otherwise exist in a solvent environment. Conclusion: Inclusion of solvent effects in MD simulations is crucial in understanding structural flexibility and stability of β-glucuronidase. Implicit solvent method can provide a realistic inclusion of backbone flexibility and structural compactness of GUS, which will have profound influence on the stability and activity of the enzymes, with a marginal increase in computational time.