The effect of pH on PAMAM dendrimer-siRNA complexation:endosomal considerations as determined by molecular dynamics simulation

Intracellular degradation of genes, most notably within the endo-lysosomal compartment is considered a significant barrier to (non-viral) gene delivery in vivo. Previous reports based on in vitro studies claim that carriers possessing a mixture of primary, secondary and tertiary amines are able to buffer the acidic environment within the endosome, allowing for timely release of their contents, leading to higher transfection rates. In this report, we adopt an atomistic molecular dynamics (MD) simulation approach, comparing the complexation of 21-bp siRNA with low-generation polyamidoamine (PAMAM) dendrimers (G0 and G1) at both neutral and acidic pHs, the latter of which mimics the degradative environment within maturing 'late-endosomes'. Our simulations reveal that the time taken for the dendrimer-gene complex (dendriplex) to reach equilibrium is appreciably longer at low pH and this is accompanied by more compact packaging of the dendriplex, as compared to simulations performed at neutral pH. We also note larger absolute values of calculated binding free energies of the dendriplex at low pH, indicating a higher dendrimer-nucleic acid affinity in comparison with neutral pH. These novel simulations provide a more detailed understanding of low molecular-weight polymer-siRNA behavior, mimicking the endosomal environment and provide input of direct relevance to the "proton sponge theory", thereby advancing the rational design of non-viral gene delivery systems.

A molecular dynamics model of the atomic structure of dysprosium alumino-phosphate glass

Molecular dynamics (MD) has been used to identify the relative distribution of dysprosium in the phosphate glass DyAl0.30P3.05O9.62. The MD model has been compared directly with experimental data obtained from neutron diffraction to enable a detailed comparison beyond the total structure factor level. The MD simulation gives Dy ... Dy correlations at 3.80(5) and 6.40(5) angstrom with relative coordination numbers of 0.8(1) and 7.3(5), thus providing evidence of minority rare-earth clustering within these glasses. The nearest neighbour Dy-O peak occurs at 2.30 angstrom with each Dy atom having on average 5.8 nearest neighbour oxygen atoms. The MD simulation is consistent with the phosphate network model based on interlinked PO4 tetrahedra where the addition of network modifiers Dy3+ depolymerizes the phosphate network through the breakage of P-(O)-P bonds whilst leaving the tetrahedral units intact. The role of aluminium within the network has been taken into explicit account, and A1 is found to be predominantly (78 tetrahedrally coordinated. In fact all four A1 bonds are found to be to P (via an oxygen atom) with negligible amounts of Al-O-Dy bonds present. This provides an important insight into the role of Al additives in improving the mechanical properties of these glasses.

Molecular dynamics simulations:bring biomolecular structures alive on a computer

The molecular dynamics (MD) simulations play a very important role in science today. They have been used successfully in binding free-energy calculations and rational design of drugs and vaccines. MD simulations can help visualize and understand structures and dynamics at an atomistic level when combined with molecular graphics programs. The molecular and atomistic properties can be displayed on a computer in a time-dependent way, which opens a road toward a better understanding of the relationship of structure, dynamics, and function. In this chapter, the basics of MD are explained, together with a step-by-step description of setup and running an MD simulation.

Why are MD simulated protein folding times wrong?

The question of significant deviations of protein folding times simulated using molecular dynamics from experimental values is investigated. It is shown that in the framework of Markov State Model (MSM) describing the conformational dynamics of peptides and proteins, the folding time is very sensitive to the simulation model parameters, such as forcefield and temperature. Using two peptides as examples, we show that the deviations in the folding times can reach an order of magnitude for modest variations of the molecular model. We, therefore, conclude that the folding rate values obtained in molecular dynamics simulations have to be treated with care.

Molecular dynamics simulation of brittle fracture in silicon

The fracture process involves converting potential energy from a strained body into surface energy, thermal energy, and the energy needed to create lattice defects. In dynamic fracture, energy is also initially converted into kinetic energy. This paper uses molecular dynamics (MD) to simulate brittle frcture in silicon and determine how energy is converted from potential energy (strain energy) into other forms.