Molecular dynamics simulations of peptide-surface interactions

Proteins, which are bioactive molecules, adsorb on implants placed in the body through complex and poorly understood mechanisms and directly influence biocompatibility. Molecular dynamics modeling using empirical force fields provides one of the most direct methods of theoretically analyzing the behavior of complex molecular systems and is well-suited for the simulation of protein adsorption behavior. To accurately simulate protein adsorption behavior, a force field must correctly represent the thermodynamic driving forces that govern peptide residue-surface interactions. However, since existing force fields were developed without specific consideration of protein-surface interactions, they may not accurately represent this type of molecular behavior. To address this concern, we developed a host-guest peptide adsorption model in the form of a G(4)-X-G(4) peptide (G is glycine, X is a variable residue) to enable determination of the contributions to adsorption free energy of different X residues when adsorbed to functionalized Au-alkanethiol self-assembled monolayers (SAMs). We have previously reported experimental results using surface plasmon resonance (SPR) spectroscopy to measure the free energy of peptide adsorption for this peptide model with X = G and K (lysine) on OH and COOH functionalized SAMs. The objectives of the present research were the development and assessment of methods to calculate adsorption free energy using molecular dynamics simulations with the GROMACS force field for these same peptide adsorption systems, with an oligoethylene oxide (OEG) functionalized SAM surface also being considered. By comparing simulation results to the experimental results, the accuracy of the selected force field to represent the behavior of these molecular systems can be evaluated. From our simulations, the G(4)-G-G(4) and G(4)-K-G(4) peptides showed minimal to no adsorption to the OH SAM surfaces and the G(4)-K-G(4) showed strong adsorption to the COOH SAM surface, which is in agreement with our SPR experiments. Contrary to our experimental results, however, the simulations predicted a relatively strong adsorption of G(4)-G-G(4) peptide to the COOH SAM surface. In addition, both peptides were unexpectedly predicted to adsorb to the OEG surface. These findings demonstrate the need for GROMACS force field parameters to be rebalanced for the simulation of peptide adsorption behavior on SAM surfaces. The developed methods provide a direct means of assessing, modifying, and validating force field performance for the simulation of peptide and protein adsorption to surfaces, without which little confidence can be placed in the simulation results that are generated with these types of systems.     

Molecular dynamics simulations of peptide carboxylate hydration

Aqueous solvation of carboxylate groups, as present in the glycine zwitterion and the dipeptide aspartylalanine, is studied employing a force-field that includes distributed multipole electrostatics and induction contributions (Amoebapro: P. Ren and J. W. Ponder, J. Comput. Chem., 2002, 23, 1497; P. Ren and J. W. Ponder, J. Phys. Chem. B, 2003, 107, 5933; J. W. Ponder and D. A. Case, Adv. Protein Chem., 2003, 66, 27). Radial and orientation distribution functions, as well as hydration numbers, are calculated and compared with existing simulation data derived from Car-Parrinello molecular dynamics (CPMD), and also distributed-charge force-fields. Connections are also made with experimental data for solvation of carboxylates in water. Our findings show that Amoebapro yields carboxylate solvation properties in very good agreement with CPMD results, significantly closer agreement than can be obtained from traditional force-fields. We also demonstrate that the influence of solvation on the conformation of the dipeptide is markedly different using Amoebapro compared with the other force-fields.     

Molecular dynamics simulations of signal transmission through a glycine peptide chain

The injection of finite duration vibrational signals encoding information into a biomolecular wire of the polypeptide glycine1000 is investigated theoretically using molecular dynamics simulations and digital signal processing techniques. We demonstrate that the amplitude modulated signal applied to one of the C-N bonds of the molecule transmits in the two directions through the long polypeptide molecule, which is connected to gold clusters at each of its ends. A decay of the signal propagation speed is observed along with intensity decay. On the other hand, the molecular dynamics simulations show that signal transmission is completely achievable at room temperature, thus realistic transmission of signals through linear molecules can be performed.     

Molecular dynamics simulations of pressure effects on hydrophobic interactions.

We report results on the pressure effects on hydrophobic interactions obtained from molecular dynamics simulations of aqueous solutions of methanes in water. A wide range of pressures that is relevant to pressure denaturation of proteins is investigated. The characteristic features of water-mediated interactions between hydrophobic solutes are found to be pressure-dependent. In particular, with increasing pressure we find that (1) the solvent-separated configurations in the solute-solute potential of mean force (PMF) are stabilized with respect to the contact configurations; (2) the desolvation barrier increases monotonically with respect to both contact and solvent-separated configurations; (3) the locations of the minima and the barrier move toward shorter separations; and (4) pressure effects are considerably amplified for larger hydrophobic solutes. Together, these observations lend strong support to the picture of the pressure denaturation process proposed previously by Hummer et al. (Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 1552): with increasing pressure, the transfer of water into protein interior becomes key to the pressure denaturation process, leading to the dissociation of close hydrophobic contacts and subsequent swelling of the hydrophobic protein interior through insertions of water molecules. The pressure dependence of the PMF between larger hydrophobic solutes shows that pressure effects on the interaction between hydrophobic amino acids may be considerably amplified compared to those on the methane-methane PMF.     

Molecular dynamics simulations and structure-based network analysis reveal structural and functional aspects of G-protein coupled receptor dimer interactions

A significant amount of experimental evidence suggests that G-protein coupled receptors (GPCRs) do not act exclusively as monomers but also form biologically relevant dimers and oligomers. However, the structural determinants, stoichiometry and functional importance of GPCR oligomerization remain topics of intense speculation. In this study we attempted to evaluate the nature and dynamics of GPCR oligomeric interactions. A representative set of GPCR homodimers were studied through Coarse-Grained Molecular Dynamics simulations, combined with interface analysis and concepts from network theory for the construction and analysis of dynamic structural networks. Our results highlight important structural determinants that seem to govern receptor dimer interactions. A conserved dynamic behavior was observed among different GPCRs, including receptors belonging in different GPCR classes. Specific GPCR regions were highlighted as the core of the interfaces. Finally, correlations of motion were observed between parts of the dimer interface and GPCR segments participating in ligand binding and receptor activation, suggesting the existence of mechanisms through which dimer formation may affect GPCR function. The results of this study can be used to drive experiments aimed at exploring GPCR oligomerization, as well as in the study of transmembrane protein–protein interactions in general.     

Molecular dynamics simulations of the interactions between platinum clusters and carbon platelets

Molecular dynamics simulations have been performed with two reactive force fields to investigate the structure of a Pt100 cluster adsorbed on the three distinct sides of a carbon platelet. A revised Reax force field for the carbon-platinum system is presented. In the simulations, carbon platelet edges both with and without hydrogen termination have been studied. It is found that the initial mismatch between the atomic structure of the platelet egde and the adsorbed face of the Pt100 cluster leads to a desorption of a few platinum atoms from the cluster and the subsequent restructuring of the cluster. Consequently, the average Pt-Pt bond length is enlarged in agreement with experimental results. This change in the bond length is supposed to play an important role in the enhancement of the catalytic activity, which is demonstrated by studying the changes in the bond order of the platinum atoms. We found an overall shift to lower values as well as a loss of the well-defined peak structure in the bond-order distribution.     

Molecular dynamics simulations of the interactions of kinin peptides with an anionic POPG bilayer

We have performed molecular dynamics simulations of peptide hormone bradykinin (BK) and its fragment des-Arg9-BK in the presence of an anionic lipid bilayer, with an aim toward delineating the mechanism of action related to their bioactivity. Starting from the initial aqueous environment, both of the peptides are quickly adsorbed and stabilized on the cell surface. Whereas BK exhibits a stronger interaction with the membrane and prefers to stay on the interface, des-Arg9-BK, with the loss of C-terminal Arg, penetrates further. The heterogeneous lipid-water interface induces β-turn-like structure in the otherwise inherently flexible peptides. In the membrane-bound state, we observed C-terminal β-turn formation in BK, whereas for des-Arg9-BK, with the deletion of Arg9, turn formation occurred in the middle of the peptide. The basic Arg residues anchor the peptide to the bilayer by strong electrostatic interactions with charged lipid headgroups. Simulations with different starting orientations of the peptides with respect to the bilayer surface lead to the same observations, namely, the relative positioning of the peptides on the membrane surface, deeper penetration of the des-Arg9-BK, and the formation of turn structures. The lipid headgroups adjacent to the bound peptides become substantially tilted, causing bilayer thinning near the peptide contact region and increase the degree of disorder in nearby lipids. Again, because of hydrogen bonding with the peptide, the neighboring lipid's polar heads exhibit considerably reduced flexibility. Corroborating findings from earlier experiments, our results provide important information about how the lipid environment promotes peptide orientation/conformation and how the peptide adapts to the environment.     

Molecular dynamics simulations reveal specific interactions of post-translational palmitoyl modifications with rhodopsin in membranes

We present a detailed analysis of the behavior of the highly flexible post-translational lipid modifications of rhodopsin from multiple-microsecond all-atom molecular dynamics simulations. Rhodopsin was studied in a realistic membrane environment that includes cholesterol, as well as saturated and polyunsaturated lipids with phosphocholine and phosphoethanolamine headgroups. The simulation reveals striking differences between the palmitoylations at Cys322 and Cys323 as well as between the palmitoyl chains and the neighboring lipids. Notably the palmitoyl group at Cys322 shows considerably greater contact with helix H1 of rhodopsin, yielding frequent chain upturns with longer reorientational correlation times, and relatively low order parameters. While the palmitoylation at Cys323 makes fewer protein contacts and has increased order compared to Cys322, it nevertheless exhibits greater flexibility with smaller order parameters than the stearoyl chains of the surrounding lipids. The dynamical structure of the palmitoylations-as well as their extensive fluctuations-suggests a complex function for the post-translational modifications in rhodopsin and potentially other G protein-coupled receptors, going beyond their role as membrane anchoring elements. Rather, we propose that the palmitoylation at Cys323 has a potential role as a lipid anchor, whereas the palmitoyl-protein interaction observed for Cys322 suggests a more specific interaction that affects the stability of the dark state of rhodopsin.     

Molecular dynamics simulations of bovine cathepsin B and its complex with CA074

To promote our better understanding of the dynamic stability of the bovine cathepsin B structure, which is characterized by an extra disulfide bond at Cys148-Cys252 from the other species, and of the binding stability of CA074 (a cathepsin B-specific inhibitor), molecular dynamics (MD) simulations were performed for the enzyme and its CA074 complex, assuming a system in aqueous solution at 300 K. The MD simulation covering 400 ps indicated that the existence of a Cys148-Cys252 disulfide bond increases the conformational flexibility of the occluding loop, although the conformational stability of the overall structure is little affected. The structural characteristics of the complex elucidated by X-ray analysis were suggested to be also intrinsic and stable in the dynamic state; the hydrogen bonding/electrostatic interactions between the main and side chains of CA074 and the Sn and Sn' subsites of the enzyme were maintained throughout the MD simulation. Furthermore, the simulation made clear that the binding of CA074 significantly restricted the conformational flexibility of the substrate binding region, especially the occluding loop, of cathepsin B. Statistical analyses during the simulation suggest that the selectivity of CA074 for cathepsin B stems from the tight P1'-S1' and P2'-S2' interactions, assisted in particular by double hydrogen bonds between the carboxyl two oxygens of the CA074 C-terminus and the imidazole NH groups of His110 and His111 residues.     

Molecular dynamics simulations of multilayer polyelectrolyte films: effect of electrostatic and short-range interactions

The effect of the strength of electrostatic and short-range interactions on the multilayer assembly of oppositely charged polyelectrolytes at a charged substrate was studied by molecular dynamics simulations. The multilayer buildup was achieved through sequential adsorption of charged polymers in a layer-by-layer fashion from dilute polyelectrolyte solutions. The strong electrostatic attraction between oppositely charged polyelectrolytes at each deposition step is a driving force behind the multilayer growth. Our simulations have shown that a charge reversal after each deposition step is critical for steady multilayer growth and that there is a linear increase in polymer surface coverage after the first few deposition steps. Furthermore, there is substantial intermixing between chains adsorbed during different deposition steps. We show that the polymer surface coverage and multilayer structure are each strongly influenced by the strength of electrostatic and short-range interactions.     

Molecular dynamics simulations of extensional,sheet and unidirectional flow

Non-equilibrium molecular dynamics, NEMD, has been used to determine the technologically important tensile viscosities. Simulations of elongational, sheet and unidirectional viscoelastic responses via the “differences-in-trajectories” technique have been made on Lennard-Jones liquid at ?* = 0.8442 and T* = 0.72, and ?* = 1.01304 and T* = 1.26. At finite strain rates (·γ* ≥ 0.1) shear thinning behavior is evident, in particular for unidirectional (“poker chip”) extensional flow. At γ ≥ 0.4 steady state unidirectional viscosities were not achieved before severe material deterioration. These trends are the result of extremely complex structural reorganisation well within the viscoelastic regime, which involved coupled component relaxation moduli along distortion direction.     

Molecular dynamics simulations of polycarbonate doped with Lemke chromophores

In the search for optimal electro-optical modulating materials we report in this work molecular dynamics simulations of polycarbonate doped with Lemke chromophores which is a promising candidate system for materials with such functionality. The simulations cover the electric field poling effects on the chromophore order at a temperature above the glass transition temperature (Tg) of the material, the cooling procedure from liquid state to the glass state in the presence of the poling field, and the back relaxation of the system after removal of the field. Our study shows that electric field poling results in a higher chromophore order and that the order is also maintained during the cooling procedure with the poling field applied. In the liquid state, the applied poling field has little effect on the structure of the material. However, after the cooling procedure, the structure changes significantly because the polymer matrix tends to become closely packed. Our study thus indicates that for the bulk material, the structure of the host matrix is very important in determining the performance of the material.     

Molecular dynamics simulations of hydrophobic and amphiphatic proteins interacting with a lipid bilayer membrane

Molecular dynamics simulations of polypeptides at high dilution near a fully hydrated bilayer membrane have been performed. In contrast to previous theoretical predictions, Monte Carlo simulations and conclusions from experiments a spontaneous insertion of amphiphatic or hydrophobic proteins into a membrane is not observed. Rather it is found that an amphiphatic chain has the tendency to remain in proximity to the membrane surface, whereas the location of a hydrophobic chain is more unbound. This is shown using two proteins, melittin and polyleucine. The conformation of the proteins and their orientation with respect to the membrane surface are discussed.     

Cation-pi interactions stabilize the structure of the antimicrobial peptide indolicidin near membranes: molecular dynamics simulations

We implemented molecular dynamics simulations of the 13-residue antimicrobial peptide indolicidin (ILPWKWPWWPWRR-NH2) in dodecylphosphocholine (DPC) and sodium dodecyl sulfate (SDS) micelles. In DPC, a persistent cation-pi interaction between TRP11 and ARG13 defined the structure of the peptide near the interface. A transient cation-pi interaction was also observed between TRP4 and the choline group on DPC lipids. We also implemented simulation of a mutant of indolicidin in the DPC micelle where TRP11 was replaced by ALA11. As a result of the mutation, the boat-shaped conformation is lost and the structure becomes significantly less defined. On the basis of this evidence, we argue that cation-pi interactions determine the experimentally measured, well-defined boat-shaped structure of indolicidin. In SDS, the lack of such interactions and the electrostatic binding of the terminal arginine residues to the sulfate groups leads to an extended peptide structure. To the best of our knowledge, this is the first time that a cation-pi interaction between peptide side chains has been shown to stabilize the structure of a small antimicrobial peptide. The simulations are in excellent agreement with available experimental measurements: the backbone of the peptide is more ordered in DPC than in SDS; the tryptophan side chains pack against the backbone in DPC and point away from the backbone in SDS; the rms fluctuation of the peptide backbone and peptide side chains is greater in SDS than in DPC; and the peptide backbone order parameters are higher in DPC than in SDS.     

Molecular dynamics simulations of structure and dynamics of organic molecular crystals

A set of model compounds covering a range of polarity and flexibility have been simulated using GAFF, CHARMM22, OPLS and MM3 force fields to examine how well classical molecular dynamics simulations can reproduce structural and dynamic aspects of organic molecular crystals. Molecular structure, crystal structure and thermal motion, including molecular reorientations and internal rotations, found from the simulations have been compared between force fields and with experimental data. The MM3 force field does not perform well in condensed phase simulations, while GAFF, CHARMM and OPLS perform very similarly. Generally molecular and crystal structure are reproduced well, with a few exceptions. The atomic displacement parameters (ADPs) are mostly underestimated in the simulations with a relative error of up to 70%. Examples of molecular reorientation and internal rotation, observed in the simulations, include in-plane reorientations of benzene, methyl rotations in alanine, decane, isopropylcyclohexane, pyramidal inversion of nitrogen in amino group and rotation of the whole group around the C-N bond. Frequencies of such dynamic processes were calculated, as well as thermodynamic properties for reorientations in benzene and alanine. We conclude that MD simulations can be used for qualitative analysis, while quantitative results should be taken with caution. It is important to compare the outcomes from simulations with as many experimental quantities as available before using them to study or quantify crystal properties not available from experiment.     

Molecular simulations of host-guest interactions between zeolite framework STW and its organic structure-directing agents

Zeolites have been widely applied in many chemical processes owing to their featured microporous framework structures. Organic structure-directing agents (OSDAs) play an important role during of the formation of zeolite frameworks via non-bonding host-guest interactions. Understanding these interactions is crucial to the design of OSDAs and the synthesis of target zeolites. Here, we report a molecular simulation study in the host-guest interactions between zeolite framework STW and 21 alkylated imidazolium and pyrazolium cations that have been used as the OSDAs for the synthesis of STW-type zeolites. We find that OSDAs that have successfully directed the formation of STW exhibit stronger host-guest interactions than unsuccessful ones. Furthermore, we find all successful OSDAs possess relatively more negative atomic charges on nitrogen atoms and smaller dipole moments. According to this finding, we have designed seven new alkylated imidazolium and pyrazolium cations that may be suitable for zeolite STW, and verified their structure-directing capability by molecular simulation calculations.     

Molecular dynamics simulations of surfactant self-organization at a solid-liquid interface

Self-organization of aqueous surfactants at a planar graphite-like surface is studied by means of coarse-grain molecular dynamics simulations. The nonionic surfactant, n-alkyl poly(ethylene oxide), and water are both represented by coarse-grain models while an implicit representation is used for the graphite surface. The observed morphology of the aggregated surfactants depends on the alkyl chain length. Surfactants with a short chain form a monolayer on the graphite surface with a thickness roughly equal to that of the alkane tail. On the other hand, longer-tail surfactants form continuous hemicylinders on the surface with diameter approximately 5.0 +/- 0.5 nm, in good agreement with experimental AFM data.     

Molecular dynamics simulations of polyelectrolyte multilayering on a charged particle

Molecular dynamics simulations of polyelectrolyte multilayering on a charged spherical particle revealed that the sequential adsorption of oppositely charged flexible polyelectrolytes proceeds with surface charge reversal and highlighted electrostatic interactions as the major driving force of layer deposition. Far from being completely immobilized, multilayers feature a constant surge of chain intermixing during the deposition process, consistent with experimental observations of extensive interlayer mixing in these films. The formation of multilayers as well as the extent of layer intermixing depends on the degree of polymerization of the polyelectrolyte chains and the fraction of charge on its backbone. The presence of ionic pairs between oppositely charged macromolecules forming layers seems to play an important role in stabilizing the multilayer film.     

Molecular dynamics simulations of a poly(p-phenylene) oligomer

We have studied the conformation and coefficient of thermal expansion in the poly(p-phenylene) oligomer p-sexiphenyl (C₃₆H₂₆) by molecular dynamics simulations. Studies of the backbone phenyl–phenyl torsion angle in a simulated p-sexiphenyl crystal at room temperature indicate the presence of torsional librations of approximately ±20°. Further analysis of the phenyl–phenyl backbone torsion angle in less closely packed regions of the simulated crystal (crystal ends) indicate the presence of 180° phenyl ring flips, in agreement with solid-state deuterium NMR data on poly(p-phenylene oligomers). The linear coefficient of thermal expansion was also calculated and found to be negative, in qualitative agreement with experimental data on rigid-rod compounds. © 1993 John Wiley & Sons, Inc.