Choice Of Force Field Research Articles

The Role of Molecular Dynamics Simulations in Elucidating Interactions between Antimicrobial Peptides and Model Biological Membranes

In addressing the global problem of antimicrobial resistance, an emerging class of molecules called antimicrobial peptides (AMPs) are being widely studied. Their interactions with cell membranes are instrumental in their killing action, usually by forming pores or translocating to act on an internal target. Molecular dynamics (MD) simulations have played an essential role in understanding the atomistic mechanisms of such interactions. This review will highlight key findings from various MD studies, such as the formation of nanoaggregates and different types of pores. We will also discuss the role of selecting the membrane model composition, the level of detail in the simulation, and the choice of force field. It is evident in this review that our understanding of the interactions of AMPs and membranes has grown over the recent years through the help of MD simulations. Still, remaining concerns in MD studies of such systems must be addressed to gain more information.

Functional protein dynamics in a crystal.

Proteins are molecular machines and to understand how they work, we need to understand how they move. New pump-probe time-resolved X-ray diffraction methods open up ways to initiate and observe protein motions with atomistic detail in crystals on biologically relevant timescales. However, practical limitations of these experiments demands parallel development of effective molecular dynamics approaches to accelerate progress and extract meaning. Here, we establish robust and accurate methods for simulating dynamics in protein crystals, a nontrivial process requiring careful attention to equilibration, environmental composition, and choice of force fields. With more than seven milliseconds of sampling of a single chain, we identify critical factors controlling agreement between simulation and experiments and show that simulated motions recapitulate ligand-induced conformational changes. This work enables a virtuous cycle between simulation and experiments for visualizing and understanding the basic functional motions of proteins.

Relative cooperativity in neutral and charged molecular clusters using QM/MM calculations.

QM/MM methods have been used to study electronic structure properties and chemical reactivity in complex molecular systems where direct electronic structure calculations are not feasible. In our previous work, we showed that non-polarizable force fields, by design, describe intermolecular interactions through pairwise interactions, overlooking many-body interactions involving three or more particles. In contrast, polarizable force fields account partially for many-body effects through polarization, but still handle van der Waals and permanent electrostatic interactions pairwise. We showed that despite those limitations, polarizable and non-polarizable force fields can reproduce relative cooperativity achieved using density functional theory due to error compensation mechanisms. In this contribution, we assess the performance of QM/MM methods in reproducing these phenomena. Our study highlights the significance of the QM region size and force field choice in QM/MM calculations, emphasizing the importance of parameter validation to obtain accurate interaction energy predictions.

Critical Evaluation of Polarizable and Nonpolarizable Force Fields for Proteins Using Experimentally Derived Nitrile Electric Fields.

Molecular dynamics (MD) simulations are frequently carried out for proteins to investigate the role of electrostatics in their biological function. The choice of force field (FF) can significantly alter the MD results, as the simulated local electrostatic interactions lack benchmarking in the absence of appropriate experimental methods. We recently reported that the transition dipole moment (TDM) of the popular nitrile vibrational probe varies linearly with the environmental electric field, overcoming well-known hydrogen bonding (H-bonding) issues for the nitrile frequency and, thus, enabling the unambiguous measurement of electric fields in proteins (J. Am. Chem. Soc. 2022, 144 (17), 7562-7567). Herein, we utilize this new strategy to enable comparisons of experimental and simulated electric fields in protein environments. Specifically, previously determined TDM electric fields exerted onto nitrile-containing o-cyanophenylalanine residues in photoactive yellow protein are compared with MD electric fields from the fixed-charge AMBER FF and the polarizable AMOEBA FF. We observe that the electric field distributions for H-bonding nitriles are substantially affected by the choice of FF. As such, AMBER underestimates electric fields for nitriles experiencing moderate field strengths; in contrast, AMOEBA robustly recapitulates the TDM electric fields. The FF dependence of the electric fields can be partly explained by the presence of additional negative charge density along the nitrile bond axis in AMOEBA, which is due to the inclusion of higher-order multipole parameters; this, in turn, begets more head-on nitrile H-bonds. We conclude by discussing the implications of the FF dependence for the simulation of nitriles and proteins in general.

Thermal conductivity of Portlandite: Molecular dynamics based approach

Energy storage provides a greener path of efficient energy utilization. Recent trends of research suggest concrete as a potential thermal energy storage (TES) material. Its cheap commercial availability makes it one of the most deserving candidates. Cement paste is the key glue of concrete, hence performance of its major components in thermal conduction seeks thorough scientific study. Portlandite or calcium hydroxide is the second major component of cement paste, microscopically visible at a scale length of <10−4 m. Molecular dynamics (MD) simulation has been utilized to investigate the thermal transport mechanism of portlandite at an atomistic scale. The thermal conductivity of this component has been computed using three major force fields which are compared with the experimental outcome using modulated differential scanning calorimetry (MDSC). It has been observed that the simulation outcomes are in order with the experimental value but the results are sensitive to the choice of force fields. Excitation of molecules during thermal transport is predominantly governed by lower-frequency molecular vibration indicating the existence of Boson Peaks. This manuscript presents the full thermal conductivity tensor of portlandite along with the possible mechanism associated with thermal transport.

Accurate Calculation of Solvation Properties of Lithium Ions in Nonaqueous Solutions.

We perform all-atom molecular dynamics simulations of lithium triflate in 1,2-dimethoxyethane using six different literature force fields. This system is representative of many experimental studies of lithium salts in solvents and polymers. We show that multiple historically common force fields for lithium ions give qualitatively incorrect results when compared with those from experiments and quantum chemistry calculations. We illustrate the importance of correctly selecting force field parameters and give recommendations on the force field choice for lithium electrolyte applications.

Evaluation of autophagy inhibition to combat cancer: (vanadium complex)-protein interactions, parameterization, and validation of a new force field.

Autophagy has drawn attention from the scientific community, mainly because of its significant advantages over chemotherapeutic processes. One of these advantages is its direct action on cancer cells, avoiding possible side effects, unlike chemotherapy, which reaches tumor cells and affects healthy cells in the body, leading to a great loss in the quality of life of patients. In this way, it is known that vanadium complex (VC) [VO(oda)(phen)] has proven inhibition effect on autophagy process in pancreatic cancer cells. Keeping that in mind, molecular dynamics (MD) simulations can be considered excellent strategies to investigate the interaction of metal complexes and their biological targets. However, simulations of this type are strongly dependent on the appropriate choice of force field (FF). Therefore, this work proposes the development of AMBER FF parameters for VC, having a minimum energy structure as a starting point, obtained through DFT calculations with B3LYP/def2-TZVP level of theory plus ECP for the vanadium atom. An MD simulation in vacuum was performed to validate the developed FF. From the structural analyses, satisfying values of VC bond lengths and angles were obtained, where a good agreement with the experimental data and the quantum reference was found. The RMSD analysis showed an average of only 0.3%. Finally, we performed docking and MD (120 ns) simulations with explicit solvent between VC and PI3K. Overall, our findings encourage new parameterizations of metal complexes with significant biological applications, as well as allow to contribute to the elucidation of the complex process of autophagy.

Influence of force field choice on the conformational landscape of rat and human islet amyloid polypeptide.

Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein (IDP) whose abnormal aggregation into toxic soluble oligomers and insoluble amyloid fibrils is a pathological feature in type-2 diabetes. Rat IAPP (rIAPP) differs from hIAPP by only six amino acids yet has a reduced tendency to aggregate or form fibrils. The structures of the monomeric forms of IAPP are difficult to characterize due to their intrinsically disordered nature. Molecular dynamics simulations can provide a detailed characterization of the monomeric forms of rIAPP and hIAPP in near-physiological conditions. In this work, the conformational landscapes of rIAPP and hIAPP as a function of secondary structure content were predicted using well-tempered bias exchange metadynamics simulations. Several combinations of commonly used biomolecular force fields and water models were tested. The predicted conformational preferences of both rIAPP and hIAPP are typical of IDPs, exhibiting dominant random coil structures but showing a low propensity for transient α-helical conformations. Predicted nuclear magnetic resonance Cα chemical shifts reveal different preferences with each force field towards certain conformations, with AMBERff99SBnmr2/TIP4Pd showing the best agreement with the experiment. Comparisons of secondary structure content demonstrate residue-specific differences between hIAPP and rIAPP that may reflect their different aggregation propensities.

Benchmarking Adaptive Steered Molecular Dynamics (ASMD) on CHARMM Force Fields.

The potentials of mean force (PMFs) along the end‐to‐end distance of two different helical peptides have been obtained and benchmarked using the adaptive steered molecular dynamics (ASMD) method. The results depend strongly on the choice of force field driving the underlying all‐atom molecular dynamics, and are reported with respect to the three most popular CHARMM force field versions: c22, c27 and c36. Two small peptides, ALA10 and 1PEF, serve as the particular case studies. The comparisons between the versions of the CHARMM force fields provides both a qualitative and quantitative look at their performance in forced unfolding simulations in which peptides undergo large changes in structural conformations. We find that ASMD with the underlying c36 force field provides the most robust results for the selected benchmark peptides.

Evaluation of implicit solvent models in molecular dynamics simulation of α-Synuclein

We report conventional and accelerated molecular dynamics simulations of α-Synuclein, designed to assess performance of using different starting conformation, solvation environment and force field combination. Backbone and sidechain chemical shifts, radius of gyration, presence of β-hairpin structures in KTK(E/Q)GV repeats and secondary structure percentages were used to evaluate how variations in forcefield, solvation model and simulation protocol provide results that correlate with experimental findings. We show that with suitable choice of forcefield and solvent, ff03ws and OBC implicit model, respectively, acceptable reproduction of experimental data on size and secondary structure is obtained by both conventional and accelerated MD. In contrast to the implicit solvent model, simulations in explicit TIP4P/2005 solvent do not properly represent size or secondary structure of α-Synuclein. Communicated by Ramaswamy H. Sarma

Using Molecular Simulation to Guide Protein Engineering for Biocatalysis in Organic Solvents.

Biocatalysis in organic solvents (OSs) is very appealing for the industry in producing bulk and/or fine chemicals, such as pharmaceuticals, biodiesel, and fragrances. The poor performance of enzymes in OSs (e.g., reduced activity, insufficient stability, and deactivation) negates OSs' excellent solvent properties. Molecular dynamics (MD) simulations provide a complementary method to study the relationship between enzymes dynamics and the stability in OSs. Here we describe computational procedure for MD simulation of enzymes in OSs with an example of Bacillus subtilis lipase A (BSLA) in dimethyl sulfoxide (DMSO) cosolvent with software GROMACS. We discuss main essential practical issues considered (such as choice of force field, parameterization, simulation setup, and trajectory analysis). The core part of this protocol (enzyme-OS system setup, analysis of structural-based and solvation-based observables) is transferable to other enzymes and any OS systems. Combining with experimental studies, the obtained molecular knowledge is most likely to guide researchers to access rational protein engineering approaches to tailor OS resistant enzymes and expand the scope of biocatalysis in OS media. Finally, we discuss potential solutions to overcome the remaining challenges of computational biocatalysis in OSs and briefly draw future directions for further improvement in this field.

Thermal Transport in Polyethylene: The Effect of Force Fields and Crystallinity

In this article, we study the local structure and heat transfer properties (thermal conductivity and interfacial conductance) in model semi-crystalline polyethylene (PE) by non-equilibrium molecular dynamics. We compare three different force fields with different levels of detail (all-atom, all-atom with constraints, and united-atom) and find that the structure of the model PE is significantly influenced by the choice of force field. The united-atom force field results in a reduced overall crystallinity and an over-idealized organization of the polymer chains, compared to the all-atom force fields. We find that thermal transport properties are not greatly influenced when structural effects are taken into consideration, and our results suggest that united-atom models can be used to study heat transfer properties of model PE, with decreased computational cost.

Choice of force fields and water models for sampling solution conformations of bacteriophage T4 lysozyme

A protein may exist as an ensemble of different conformations in solution, which cannot be represented by a single static structure. Molecular dynamics (MD) simulation has become a useful tool for sampling protein conformations in solution, but force fields and water models are important issues. This work presents a case study of the bacteriophage T4 lysozyme (T4L). We have found that MD simulations using a classic AMBER99SB force field and TIP4P water model cannot well describe hinge-bending domain motion of the wild-type T4L at the timescale of one microsecond. Other combinations, such as a residue-specific force field called RSFF2+ and a dispersion-corrected water model TIP4P-D, are able to sample reasonable solution conformations of T4L, which are in good agreement with experimental data. This primary study may provide candidates of force fields and water models for further investigating conformational transition of T4L.

Fast Estimation of the Blood-Brain Barrier Permeability by Pulling a Ligand through a Lipid Membrane.

The blood–brain barrier (BBB) is a physical barrier that regulates the homeostasis of the neural microenvironment. A relative estimate of the BBB permeability, which is important for drug design, may be experimentally provided by the logBB (the blood–brain concentration ratio) and the logPS (permeability–surface-area product), while many computational methods aim to identify key properties that correlate well with these quantities. Although currently existing computational methods (e.g., quantitative structure activity relation) have made a significant contribution in screening various compounds that could potentially translocate through the BBB, they are unable to provide a physical explanation of the underlying processes and they can often be computationally demanding. Here, we use steered molecular dynamics simulation to estimate the BBB permeability of various compounds on the basis of simple lipid–membrane models by computing the nonequilibrium work, Wneq, produced by pulling the compounds through the membrane. We found that the values of Wneq correlate remarkably well with logBB and logPS for a range of compounds and different membrane types and pulling speeds, independently of the choice of force field. Moreover, our results provide insight into the role of hydrogen bonds, the energetic barriers, and the forces exerted on the ligands during their pulling. Our method is computationally easy to implement and fast. Therefore, we anticipate that it could provide a reliable prescreening tool for estimating the relative permeability of the BBB to various substances.

The Effect of Force-Field Parameters on Cytochrome P450-Membrane Interactions: Structure and Dynamics

The simulation of membrane proteins requires compatible protein and lipid force fields that reproduce the properties of both the protein and the lipid bilayer. Cytochrome P450 enzymes are bitopic membrane proteins with a transmembrane helical anchor and a large cytosolic globular domain that dips into the membrane. As such, they are representative and challenging examples of membrane proteins for simulations, displaying features of both peripheral and integral membrane proteins. We performed molecular dynamics simulations of three cytochrome P450 isoforms (2C9, 2C19 and 1A1) in a 2-oleoyl-1-palmitoyl-sn-glycerol-3-phosphocholine bilayer using two AMBER force field combinations: GAFF-LIPID with ff99SB for the protein, and LIPID14 with ff14SB for the protein. Comparison of the structural and dynamic properties of the proteins, the lipids and the protein-membrane interactions shows differing sensitivity of the cytochrome P450 isoforms to the choice of force field, with generally better agreement with experiment for the LIPID14 + ff14SB combination.

Choice of Force Field for Proteins Containing Structured and Intrinsically Disordered Regions

Biomolecular force fields optimized for globular proteins fail to properly reproduce properties of intrinsically disordered proteins. In particular, parameters of the water model need to be modified to improve applicability of the force fields to both ordered and disordered proteins. Here, we compared performance of force fields recommended for intrinsically disordered proteins in molecular dynamics simulations of three proteins differing in the content of ordered and disordered regions (two proteins consisting of a well-structured domain and of a disordered region with and without a transient helical motif and one disordered protein containing a region of increased helical propensity). The obtained molecular dynamics trajectories were used to predict measurable parameters, including radii of gyration of the proteins and chemical shifts, residual dipolar couplings, paramagnetic relaxation enhancement, and NMR relaxation data of their individual residues. The predicted quantities were compared with experimental data obtained within this study or published previously. The results showed that the NMR relaxation parameters, rarely used for benchmarking, are particularly sensitive to the choice of force-field parameters, especially those defining the water model. Interestingly, the TIP3P water model, leading to an artificial structural collapse, also resulted in unrealistic relaxation properties. The TIP4P-D water model, combined with three biomolecular force-field parameters for the protein part, significantly improved reliability of the simulations. Additional analysis revealed only one particular force field capable of retaining the transient helical motif observed in NMR experiments. The benchmarking protocol used in our study, being more sensitive to imperfections than the commonly used tests, is well suited to evaluate the performance of newly developed force fields.

Comparison of CHARMM and OPLS-aa forcefield predictions for components in one model asphalt mixture

Molecular dynamics simulations have been widely applied to understand the effect of chemical composition on the major physical and mechanical properties and micro-structure of asphalt. However, the choice of forcefields has been mostly empirical. In this project, two commonly used forcefields, the Chemistry at Harvard Macromolecular Mechanics (CHARMM) forcefield and the Optimized Potentials for Liquid Simulations in all atom version (OPLS-aa) forcefield were evaluated, side by side for simulation of the three main components of one model asphalt mixture to compare the effectiveness of the forcefields. The CHARMM forcefield parameters for two smaller components —including n-docosane and 1,7-dimethylnaphthalene molecules—were obtained using the CGENFF program; the forcefield parameters for an average asphaltene molecule were obtained with the VMD forcefield toolkit and Gaussian quantum calculations. Comparing molecule structures of asphaltene, 1,7-dimethylnaphthalene and n-docosane (n-C22) predicted using the CHARMM forcefield to those from traditional OPLS-aa forcefield, the energy-minimized structures are very similar. At a high temperature such as 300 K and above, slight bending on the aromatic ring regions and the alkane chains was observed for the asphaltene molecule; kinking of the n-docosane molecule chain structure was also observed using both forcefields; and the structure of 1,7-dimethylnaphthalene is consistent at both low and high temperatures. Comparing the properties predicted based on the long-term simulation trajectories, the density, diffusion coefficient and g(r) result of asphaltene, 1,7-dimethylnaphthalene and n-docosane from the CHARMM and Nanoscale Molecular Dynamics (NAMD) program are very close to those from the OPLS-aa forcefield and LAMMPS program. However, the CHARMM forcefield correctly predicted the crystallization of n-docosane at 300 K while the OPLS-aa forcefield did not.

Obtaining Protein Association Energy Landscape for Integral Membrane Proteins.

Integral membrane proteins are ubiquitous in biological cellular and subcellular membranes. Despite their significance to cell function, isolation of membrane proteins from their hydrophobic lipid environment and further characterization remains a challenge. To obtain insights into membrane proteins, computational approaches such as docking or self-assembly simulations have been used; however, the promise of these approaches has been limited due to the computational cost. Here we present a new approach called Protein AssociatioN Energy Landscape (PANEL) that provides an extensive and converged data set for all possible conformations of membrane protein associations using a combination of stochastic sampling and equilibration simulations. The PANEL method samples the rotational space around both interacting proteins to obtain the comprehensive interaction energy landscape. We demonstrate the versatility of the PANEL method using two distinct applications: (a) dimerization of claudin-5 tight junction proteins in phospholipid bilayer membrane and (b) dimer and trimer formation of the Outer membrane protein F (OmpF) in the lipopolysaccharide-rich bacterial outer membrane. Both applications required only a fraction of simulation cost compared to self-assembly simulations. The method is robust as it can capture changes in protein-protein conformations caused by point mutations. Moreover, the method is versatile and independent of the molecular resolution (atomistic or coarse grain) or the choice of force field employed to compute the pair-interaction energies. The PANEL method is implemented in easy-to-use scripts that are available for download for general use by the scientific community to characterize any pair of interacting integral membrane proteins.

Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor.

Whether recent updates and new releases of atomistic force fields can model the structural and dynamical properties of proteins containing both folded and partially disordered domains is still unclear. To address this fundamental question, we tested eight recently released force fields against our set of nuclear magnetic resonance (NMR) observables for a complex and medically relevant system, the major factor VIII binding region on the von Willebrand factor. This biomedically important region comprises both a folded and a partially structured domain. By using an enhanced sampling technique (temperature replica-exchange molecular dynamics simulations), we find that some force fields indeed rise to the challenge and capture the structural and dynamical features of the NMR ensemble and, therefore, are the appropriate choice for simulations of proteins with partially structured domains. What is more, we show that only such force fields can qualitatively capture the effects of a pathogenic mutation on the structural ensemble.

Characterisation of the Structure and Oligomerisation of Islet Amyloid Polypeptides (IAPP): A Review of Molecular Dynamics Simulation Studies.

Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein whose abnormal aggregation into amyloid fibrils is a pathological feature in type 2 diabetes, and its cross-aggregation with amyloid beta has been linked to an increased risk of Alzheimer’s disease. The soluble, oligomeric forms of hIAPP are the most toxic to β-cells in the pancreas. However, the structure of these oligomeric forms is difficult to characterise because of their intrinsic disorder and their tendency to rapidly aggregate into insoluble fibrils. Experimental studies of hIAPP have generally used non-physiological conditions to prevent aggregation, and they have been unable to describe its soluble monomeric and oligomeric structure at physiological conditions. Molecular dynamics (MD) simulations offer an alternative for the detailed characterisation of the monomeric structure of hIAPP and its aggregation in aqueous solution. This paper reviews the knowledge that has been gained by the use of MD simulations, and its relationship to experimental data for both hIAPP and rat IAPP. In particular, the influence of the choice of force field and water models, the choice of initial structure, and the configurational sampling method used, are discussed in detail. Characterisation of the solution structure of hIAPP and its mechanism of oligomerisation is important to understanding its cellular toxicity and its role in disease states, and may ultimately offer new opportunities for therapeutic interventions.