Examination of the folding of a short alanine-based helical peptide with salt bridges using molecular dynamics simulation

A molecular dynamics simulation of the folding of a short alanine-based helical peptide of 17 residues with three Glu...Lys (i, i + 4) salt bridge pairs, referred to as the AEK17 peptide, was carried out. The simulation gave an estimated simulation folding time of 2.5 ns, shorter than 12 ns for an alanine-based peptide of 16 residues with three Lys residues only, referred to as the AK16 peptide, simulated previously. After folded, the AEK17 peptide had a helical content of 77%, in excellent agreement with the experimentally determined value of 80%. An examination of the folding pathways of AEK17 indicated that the peptide proceeded via three-turn helix conformations more than the helix-turn-helix conformation in the folding pathways. An analysis of interactions indicated that the formation of hydrogen bonds between Lys residue side chains and backbone carbonyls is a major factor in the abundant conformation of the three-turn helix intermediate. The substitution of three Ala with Glu residues reduces the extent of hydrophobic interaction in alanine-based AK peptides with the result that the breaking of the interactions of Lys epsilon-NH3+(side chain)...C=O(backbone) is a major activation action for the AEK17 to achieve a complete fold, in contrast to the AK16 peptide, in which breaking non-native hydrophobic interaction is the rate-determining step.     

Molecular dynamics with helical periodic boundary conditions

Helical symmetry is often encountered in nature and thus also in molecular dynamics (MD) simulations. In many cases, an approximation based on infinite helical periodicity can save a significant amount of computer time. However, standard simulations with the usual periodic boundary conditions (PBC) are not easily compatible with it. In the present study, we propose and investigate an algorithm comprising infinitely propagated helicity, which is compatible with commonly used MD software. The helical twist is introduced as a parametric geometry constraint, and the translational PBC are modified to allow for the helical symmetry via a transitional solvent volume. The algorithm including a parallel code was implemented within the Tinker software. The viability of the helical periodic boundary conditions (HPBC) was verified in test simulations including α‐helical and polyproline II like peptide structures. For an insulin‐based model, the HPBC dynamics made it possible to simulate a fibrillar structure, otherwise not stable within PBC. © 2014 Wiley Periodicals, Inc.     

Effects of osmolytes on the helical conformation of model peptide: molecular dynamics simulation

Co-solvents such as glycerol and sorbitol are small organic molecules solvated in the cellular solutions that can have profound effects on the protein structures. Here, the molecular dynamics simulations and comparative structural analysis of magainin, as a peptide model, in pure water, 2,2,2-trifluoroethanol∕water, glycerol∕water, and sorbitol∕water are reported. Our results show that the peptide NMR structure is largely maintained its native structure in osmolytes-water mixtures. The simulation data indicates that the stabilizing effect of glycerol and sorbitol is induced by preferential accumulation of glycerol and sorbitol molecules around the nonpolar and aromatic residues. Thus, the presence of glycerol and sorbitol molecules decreases the interactions of water molecules with the hydrophobic residues of the peptide, and the alpha helical structure is stabilized.     

Molecular simulation of protein dynamics in nanopores. I. Stability and folding

Discontinuous molecular dynamics simulations, together with the protein intermediate resolution model, an intermediate-resolution model of proteins, are used to carry out several microsecond-long simulations and study folding transition and stability of alpha-de novo-designed proteins in slit nanopores. Both attractive and repulsive interaction potentials between the proteins and the pore walls are considered. Near the folding temperature T(f) and in the presence of the attractive potential, the proteins undergo a repeating sequence of folding/partially folding/unfolding transitions, with T(f) decreasing with decreasing pore sizes. The unfolded states may even be completely adsorbed on the pore's walls with a negative potential energy. In such pores the energetic effects dominate the entropic effects. As a result, the unfolded state is stabilized, with a folding temperature T(f) which is lower than its value in the bulk and that, compared with the bulk, the folding rate decreases. The opposite is true in the presence of a repulsive interaction potential between the proteins and the walls. Moreover, for short proteins in very tight pores with attractive walls, there exists an unfolded state with only one alpha-helical hydrogen bond and an energy nearly equal to that of the folded state. The proteins have, however, high entropies, implying that they cannot fold onto their native structure, whereas in the presence of repulsive walls the proteins do attain their native structure. There is a pronounced asymmetry between the two termini of the protein with respect to their interaction with the pore walls. The effect of a variety of factors, including the pore size and the proteins' length, as well as the temperature, is studied in detail.     

Mechanisms of amphipathic helical peptide denaturation by guanidinium chloride and urea: a molecular dynamics simulation study

Urea and GdmCl are widely used to denature proteins at high concentrations. Here, we used MD simulations to study the denaturation mechanisms of helical peptide in different concentrations of GdmCl and urea. It was found that the helical structure of the peptide in water simulation is disappeared after 5 ns while the helicity of the peptide is disappeared after 70 ns in 2 M urea and 25 ns in 1 M GdmCl. Surprisingly, this result shows that the helical structure in low concentration of denaturants is remained more with respect to that solvated in water. The present work strongly suggests that urea interact more preferentially to non-polar and aromatic side chains in 2 M urea; therefore, hydrophobic residues are in more favorable environment in 2 M urea. Our results also reveal that the hydrogen bonds between urea and the backbone is the dominant mechanism by which the peptide is destabilized in high concentration of urea. In 1 M and 2 M GdmCl, GdmCl molecules tend to engage in transient stacking interactions with aromatics and hydrophobic planar side chains that lead to displacement of water from the hydration surface, providing more favorable environment for them. This shows that accumulation of GdmCl around hydrophobic surfaces in 1 M and 2 M GdmCl solutions prevents proper solvation of the peptide at the beginning. In high GdmCl concentrations, water solvate the peptide better than 1 M and 2 M GdmCl. Therefore, our results strongly suggest that hydrogen bonds between water and the peptide are important factors in the destabilization of peptide in GdmCl solutions.     

Folding kinetics of a naturally occurring helical peptide: implication of the folding speed limit of helical proteins

The folding mechanism and dynamics of a helical protein may strongly depend on how quickly its constituent alpha-helices can fold independently. Thus, our understanding of the protein folding problem may be greatly enhanced by a systematic survey of the folding rates of individual alpha-helical segments derived from their parent proteins. As a first step, we have studied the relaxation kinetics of the central helix (L9:41-74) of the ribosomal protein L9 from the bacterium Bacillus stearothermophilus , in response to a temperature-jump ( T-jump) using infrared spectroscopy. L9:41-74 has been shown to exhibit unusually high helicity in aqueous solution due to a series of side chain-side chain interactions, most of which are electrostatic in nature, while still remaining monomeric over a wide concentration range. Thus, this peptide represents an excellent model system not only for examining how the folding rate of naturally occurring helices differs from that of the widely studied alanine-based peptides, but also for estimating the folding speed limit of (small) helical proteins. Our results show that the T-jump induced relaxation rate of L9:41-74 is significantly slower than that of alanine-based peptides. For example, at 11 degrees C its relaxation time constant is about 2 micros, roughly seven times slower than that of SPE(5), an alanine-rich peptide of similar chain length. In addition, our results show that the folding rate of a truncated version of L9:41-74 is even slower. Taken together, these results suggest that individual alpha-helical segments in proteins may fold on a time scale that is significantly slower than the folding time of alanine-based peptides. Furthermore, we argue that the relaxation rate of L9:41-74 measured between 8 and 45 degrees C provides a realistic estimate of the ultimate folding rate of (small) helical proteins over this temperature range.     

Molecular dynamics simulation study of the water-mediated interaction between zwitterionic and charged surfaces

We calculated the potential of mean force (PMF) for the interaction between a model zwitterionic bilayer and a model charged bilayer. To understand the role of water, we separated the PMF into two components: one due to direct interaction and the other due to water-mediated interaction. In our calculations, we observed that water-mediated interaction is attractive at larger distances and repulsive at shorter. The calculation of the entropic and enthalpic contributions to the solvent-mediated components of the PMF showed that attraction is entropically dominant, while repulsion is dominated by the enthalpy.     

Molecular rectification of a helical peptide with a redox group in the metal-molecule-metal junction

A helical hexadecapeptide immobilized on gold via a thiophenyl group at the N-terminal was analyzed by scanning tunneling microscopy under ultrahigh vacuum to obtain the I-V response at a molecular level. The attenuation factor of the electron transfer through the hexadecapeptide was determined by applying the Simons model to the I-V response to show better molecular conductance of the hexadecapeptide than dodecanethiol. Chemical modification at the C-terminal of the hexadecapeptide with a ferrocene unit, on the other hand, brought about significant changes in the I-V response, where the helical peptide became more conductive at the negative bias voltage. The molecular rectification behavior is due to the ferrocene unit regulating the direction of the electron transfer at the metal-molecule junction.     

Molecular dynamics simulation studies of the transport and adsorption of a charged macromolecule onto a charged adsorbent solid surface immersed in an electrolytic solution

Molecular dynamics simulations were performed in order to study the transport and adsorption of a charged macromolecule (desmopressin) onto a charged solid surface in an electrolytic solution. The strong Coulombic interaction from the charged solid surface represents the major force for accelerating, orienting, entrapping in the electrical double layer, and adsorbing the macromolecule onto the charged solid surface. The macromolecule is flattened as it approaches the charged surface, giving rise to a stronger surface exclusion effect that shields surface sites. When adsorbed, the macromolecule is restrained by a surface interaction more than one hundred times stronger than the thermal energy, of which 99.8% results from the strong dominant Coulombic interaction, and trapped by a hydration layer adjacent to the surface. This leads to zero lateral displacement of the adsorbed macromolecule and indicates that surface diffusion is a physically implausible mechanism in similar systems. Explicit solvent is required for realistic representation of the macromolecular structure and the surface interaction energy. The adsorbed macromolecule also decreased the electrostatic potential gradient perpendicular to the charged solid surface and introduced additional electrostatic potential gradients laterally. The results obtained from the molecular dynamics simulations confirm the importance of electrophoretic migration and support the physical mechanisms used in a macroscopic continuum model that predicts an overshoot in the concentration of a charged macromolecule in the adsorbed phase under certain conditions of pH and ionic strength.     

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 bottle brushes in a solution of semiflexible polyelectrolytes and block copolymers with an oppositely charged block: a molecular dynamics simulation

Using a coarse-grained model, we performed molecular dynamics simulations of the electrostatically driven self-assembly of strongly charged polyelectrolytes and diblock copolymers composed of oppositely charged and neutral blocks. Stoichiometric micelle-like complexes formed in a dilute solution represent cylindrical brushes whose conformation is determined by the linear charge density on the polyelectrolyte and by temperature. The core-shell morphology of the cylindrical brushes is proven. The core of these anisotropic micelles consists of an insoluble complex coacervate formed by the ionic chains and a shell made up of the neutral solvophilic blocks. As the concentration of macromolecules increases, the orientational ordering of ionic micelles takes place. The complexation can induce effective steric stiffening of the polyelectrolyte chains.     

Molecular dynamics simulation with stochastically constrained pressure

The authors propose a new algorithm for molecular dynamics simulation. The method includes a Monte Carlo scheme for incrementing the dilation rate in the equations of motion. The new algorithm needs no extra computation and the dynamics of the system preserves its continuity. Application of this approach is very advantageous for models where the derivation and the computation of the pressure is time consuming. The authors present results of model calculations.     

Solvent-mediated folding of a doubly charged anion

The microsolvation of the suberate dianion, -O2C(CH2)6CO2-, with two separate charge centers was studied by photoelectron spectroscopy and molecular dynamics simulation one solvent molecule at a time for up to 20 waters. It is shown that the two negative charges are solvated in the linear suberate alternately. As the solvent number increases, the negative charges are screened and a conformation change occurs at 16 waters, where the cooperative hydrogen bonding of water is large enough to overcome the Coulomb repulsion and pull the two negative charges closer through a water bridge. This conformation change, revealed both from the experiment and from the simulation, is a manifestation of the hydrophilic and hydrophobic forces at the molecular level.     

不同链长烷烃在碳纳米管表面行为的分子动力学模拟

采用分子动力学方法模拟了不同长度的烷烃在单壁碳纳米管表面的吸附和取向过程,直观地给出了过程中很多微观信息,如链与纳米管管轴的夹角,链的弯曲程度等.结果表明短链烷烃能够被吸附在纳米管表面并沿着特定的方向取向;碳纳米管表面起到诱导取向的作用,并且该诱导作用对离表面最近的吸附层作用最明显;在吸附过程中,烷烃链发生弯曲,而吸附以后,取向的烷烃链倾向于采取伸直的状态。     

Molecular dynamics simulations of the helical antimicrobial peptide ovispirin-1 in a zwitterionic dodecylphosphocholine micelle: insights into host-cell toxicity

We have carried out a 40-ns all-atom molecular dynamics simulation of the helical antimicrobial peptide ovispirin-1 (OVIS) in a zwitterionic diphosphocholine (DPC) micelle. The DPC micelle serves as an economical and effective model for a cellular membrane owing to the presence of a choline headgroup, which resembles those of membrane phospholipids. OVIS, which was initially placed along a micelle diameter, diffuses out to the water-DPC interface, and the simulation stabilizes to an interface-bound steady state in 40 ns. The helical content of the peptide marginally increases in the process. The final conformation, orientation, and the structure of OVIS are in excellent agreement with the experimentally observed properties of the peptide in the presence of lipid bilayers composed of 75% zwitterionic lipids. The amphipathic peptide binds to the micelle with its hydrophobic face buried in the micellar core and the polar side chains protruding into the aqueous phase. There is overwhelming evidence that points to the significant and indispensable participation of hydrophobic residues in binding to the zwitterionic interface. The simulation starts with a conformation that is unbiased toward the final experimentally known binding state of the peptide. The ability of the model to reproduce experimental binding states despite this starting conformation is encouraging.