Lianghui Gao

Theoretical insight into the relationship between the structures of antimicrobial peptides and their actions on bacterial membranes.

Antimicrobial peptides with diverse cationic charges, amphiphathicities, and secondary structures possess a variety of antimicrobial activities against bacteria, fungi, and other generalized targets. To illustrate the relationship between the structures of these peptide and their actions at microscopic level, we present systematic coarse-grained dissipative particle dynamics simulations of eight types of antimicrobial peptides with different secondary structures interacting with a lipid bilayer membrane. We find that the peptides use multiple mechanisms to exert their membrane-disruptive activities: A cationic charge is essential for the peptides to selectively target negatively charged bacterial membranes. This cationic charge is also responsible for promoting electroporation. A significant hydrophobic portion is necessary to disrupt the membrane through formation of a permeable pore or translocation. Alternatively, the secondary structure and the corresponding rigidity of the peptides determine the pore structure and the translocation pathway.

Semi-bottom-up coarse graining of water based on microscopic simulations

The generalized dissipative particle dynamics (DPD) equation derived from the generalized Langevin equation under Markovian approximations is used to simulate coarse-grained (CG) water cells. The mean force and the friction coefficients in the radial and transverse directions needed for DPD equation are obtained directly from the all atomistic molecular dynamics (AAMD) simulations. But the dissipative friction forces are overestimated in the Markovian approximation, which results in wrong dynamic properties for the CG water in the DPD simulations. To account for the non-Markovian dynamics, a rescaling factor is introduced to the friction coefficients. The value of the factor is estimated by matching the diffusivity of water. With this semi-bottom-up mapping method, the radial distribution function, the diffusion constant, and the viscosity of the coarse-grained water system computed with DPD simulations are all in good agreement with AAMD results. It bridges the microscopic level and mesoscopic level with consistent length and time scales.

Self-Assembly of Lamellar Lipid−DNA Complexes Simulated by Explicit Solvent Counterion Model

The dissipative particle dynamics simulations with explicit solvent and counterions are used to mimic the self-assembly of lamellar cationic lipid-DNA (CL-DNA)complexes. We found that the formation of the complexes is associated with the releasing of 70% DNA counterions and 90% lipid counterions. The trapped DNA and CL charges together with their counterions inside the complex still keep the interior neutral, which stabilized the structure. Simulations in constant pressure ensemble following the self-assembly show that the DNA interaxial spacing as a function of the inversed CL concentrations 1/phi(c) is linear at low phi(c) and nonlinear at high phi(c). The attraction between the DNA and the CLs as well as the repulsion between the DNA strands impose stretching stress on the membrane so that the averaged area per lipid is dependent on the CL concentration, which in turn determines the behavior of the DNA spacing.

Communications: Self-energy and corresponding virial contribution of electrostatic interactions in dissipative particle dynamics: Simulations of cationic lipid bilayers

General expressions of self-energy and corresponding virial terms for electrostatic interactions in dissipative particle dynamics simulations are derived in this article. In the lattice-sum electrostatics, we found the essential process is to solve the electric field equation of each individual point charge. Strong inward pressure caused by the self-energy is eliminated by subtracting the corresponding virial from the total virial. The resulting method is tested by simulating cationic lipid bilayers in constant pressure ensemble.

Nanodomain Formation of Ganglioside GM1 in Lipid Membrane: Effects of Cholera Toxin-Mediated Cross-Linking.

Cross-linking of specific lipid components by proteins mediates transmembrane signaling and material transport. In this work, we conducted coarse-grained simulation to investigate the interactions of binding units of chorela toxin (CTB) with mixed ganglioside GM1 and dipalmitoylphosphatidylcholine (DPPC) lipid bilayer membrane. We determine that the binding of CTB pentamers cross-links GM1 molecules into protein-sized nanodomains that have distinct lipid order compared with the bulk. The toxin in the nanodomain partially penetrates into the membrane. The local disordering can also transmit across the membrane via lipid coupling. Comparison simulations on CTB binding to a membrane that is composed of various lipid components demonstrate that several factors are responsible for the nanodomain formation: (a) the negatively charged headgroup of a GM1 receptor is responsible for the multivalent binding; (b) the head groups being full of hydrogen-bonding donors and receptors stabilize the GM1 cluster itself and ensure the toxin binding with high affinity; and

Effects of Antimicrobial Peptide Revealed by Simulations: Translocation, Pore Formation, Membrane Corrugation and Euler Buckling

We explore the effects of the peripheral and transmembrane antimicrobial peptides on the lipid bilayer membrane by using the coarse grained Dissipative Particle Dynamics simulations. We study peptide/lipid membrane complexes by considering peptides with various structure, hydrophobicity and peptide/lipid interaction strength. The role of lipid/water interaction is also discussed. We discuss a rich variety of membrane morphological changes induced by peptides, such as pore formation, membrane corrugation and Euler buckling.

Theoretical insight into the photodegradation of a disulfide bridged cyclic tetrapeptide in solution and subsequent fast unfolding-refolding events

We report the photoinduced peptide bond (C-N) of an amide unit and S-S bond fission mechanisms of the cyclic tetrapeptide [cyclo(Boc-Cys-Pro-Aib-Cys-OMe)] in methanol solvent by using high-level CASSCF/CASPT2/Amber quantum mechanical/molecular mechanical (QM/MM) calculations. The subsequent energy transport and unfolding-refolding events are characterized by using a semiempirical QM/MM molecular dynamics (MD) simulation methodology that is developed in the present work. In the case of high-energy excitation with <193 nm light, the tetrapeptide molecule in the (1)n pi* surface overcomes two barriers with approximately 10.0 kcal/mol, respectively, and uses energy consumption for breaking the hydrogen bond as well as the N-C bond in the amide unit, ultimately leading to the ground state via a conical intersection of CI (S(NP)/S(0)) by structural changes of an increased N-C distance and a O-C-C angle in the amide unit (a two-dimensional model of the reaction coordinates). Following this point, relaxation to a hot molecule with its original structure in the ground state is the predominant decay channel. A large amount of heat (approximately 110.0 kcal/mol) is initially accumulated in the region of the targeted point of the photoexcitation, and more than 60% of the heat is rapidly dissipated into the solvent on the femtosecond time scale. The relatively slower propagation of heat along the peptide backbone reaches a phase of equilibration within 3 ps. A 300 nm photon of light initiates the relaxation along the repulsive S(sigma sigma)((1)sigma sigma*) state and this decays to the CI (S(sigma sigma)/S(0)) in concomitance with the separation of the disulfide bond. Once cysteinyl radicals are generated, the polar solvent of methanol molecules rapidly diffuses around the radicals, forming a solvent cage and reducing the possibility of close contact in a physical sense. The fast unfolding-refolding event is triggered by S-S bond fission and powered by dramatic thermal motion of the methanol solvent that benefits from heat dissipation. The beta-turn opening (unfolding) can be achieved in about 120 ps without the inclusion of the time associated with the photochemical steps and eventually relaxes to a 3(10)-helix structural architecture (refolding) within 200 ps.

Mechanism of Inhibition of Human Islet Amyloid Polypeptide-Induced Membrane Damage by a Small Organic Fluorogen

Human islet amyloid polypeptide (hIAPP) is believed to be responsible for the death of insulin-producing β-cells. However, the mechanism of membrane damage at the molecular level has not been fully elucidated. In this article, we employ coarse- grained dissipative particle dynamics simulations to study the interactions between a lipid bilayer membrane composed of 70% zwitterionic lipids and 30% anionic lipids and hIAPPs with α-helical structures. We demonstrated that the key factor controlling pore formation is the combination of peptide charge-induced electroporation and peptide hydrophobicity-induced lipid disordering and membrane thinning. According to these mechanisms, we suggest that a water-miscible tetraphenylethene BSPOTPE is a potent inhibitor to rescue hIAPP-induced cytotoxicity. Our simulations predict that BSPOTPE molecules can bind directly to the helical regions of hIAPP and form oligomers with separated hydrophobic cores and hydrophilic shells. The micelle-like hIAPP-BSPOTPE clusters tend to be retained in the water/membrane interface and aggregate therein rather than penetrate into the membrane. Electrostatic attraction between BSPOTPE and hIAPP also reduces the extent of hIAPP binding to the anionic lipid bilayer. These two modes work together and efficiently prevent membrane poration.

Self-assembly of gold nanorods coated with phospholipids: a coarse-grained molecular dynamics study.

The self-assembly of phospholipid-coated gold nanorods (GNRs) was investigated by coarse-grained molecular dynamics simulations. We predict that in addition to the formation of deformed vesicles encapsulating GNRs with diverse orientations, the lipid-coated GNRs can form a semi-ring attached to an excess vesicle phase, a branch with excess vesicle phase, a ring phase, a branch phase, a stack phase, and a vortex phase. The morphologies of the lipid-GNR complexes depend on the lipid/GNR molar ratio and the interaction strength between the nanorod surface and the lipid head groups. At given lipid-nanorod interactions, removing the lipid induces a phase transition from an isolated ring or branch phase to an aggregated vortex or stack phase and vice versa. As the lipid-coated GNRs transit from an isolated phase to an aggregated phase, the structure of the lipid at the nanorod surface converts from a bilayer state to a non-bilayer state.

Dissipative Particle Dynamics Simulations for Phospholipid Membranes Based on a Four-To-One Coarse-Grained Mapping Scheme.

In this article, a new set of parameters compatible with the dissipative particle dynamics (DPD) force field is developed for phospholipids. The coarse-grained (CG) models of these molecules are constructed by mapping four heavy atoms and their attached hydrogen atoms to one bead. The beads are divided into types distinguished by charge type, polarizability, and hydrogen-bonding capacity. First, we derive the relationship between the DPD repulsive force and Flory-Huggins χ-parameters based on this four-to-one CG mapping scheme. Then, we optimize the DPD force parameters for phospholipids. The feasibility of this model is demonstrated by simulating the structural and thermodynamic properties of lipid bilayer membranes, including the membrane thickness, the area per lipid, the lipid tail orientation, the bending rigidity, the rupture behavior, and the potential of mean force for lipid flip-flop.