We have systematically evaluated the ability of molecular dynamics simulation with implicit solvation models (EEF1.1, SASA, ASPENR, SCPISM, RUSH, ACE2, GBORN, GBSW, GBMV II, FACTS) to characterize the unfolding of the amyloid beta (Aβ) peptide and the stabilizing effects of mutations and ligands. The 13-26 region of Aβ (Aβ13-26) unfolds and leads to the formation of amyloid fibrils, the causative agent of Alzheimer's disease. Stabilization of Aβ13-26 decreases Aβ polymerization as well as the formation of intermediate structures, which may also be toxic. The unfolding behavior of wild-type Aβ13-26 with an increase in temperature led us to select GBORN, GBMV II, and SCPISM for further investigation considering their ability to reproduce the stabilizing effect on the Aβ13-26 helical conformation due to mutations (V18A/F19A/F20A and V18L/F19L/F20L) and ligands (Dec-DETA and Pep1b) designed to stabilize Aβ13-26. Structural parameters (RMSD, helicity) of the peptide were used to assess the performance of the implicit solvent models with reference to previous explicit solvent simulations.

Experiments show that a ligand-receptor complex formed by binding a bivalent ligand (D) in which the two ligating units are joined covalently by a flexible polymeric spacer (S) can be orders of magnitude more stable than the corresponding complex formed with monomeric ligands. Although molecular models rationalizing this "enhancement effect" have been proffered, they ignore spacer-receptor (S-R) interactions, which can substantially influence the relative stability of complexes. Here, the results of a computational study designed to assess the impact of S-R interactions in the prototypic bivalent complex are presented and compared to results of experiments. The S-R interactions mimicking general features of biological systems are modeled by contoured R surfaces with hills (or depressions) at the binding sites. In the fictitious limit of vanishing S-R interactions, the enhancement is pronounced, as observed in experiments. For strictly repulsive S-R interactions (hard R surface), the enhancement vanishes, or even reverses. This is particularly the case if the R surface is convex (i.e., rising between the binding sites), while the enhancement is only moderately reduced if the R surface is concave. Alternatively, a weak S-R attraction close to the R surface can increase the enhancement. It is concluded that large enhancement should be observed only if both features are present: a concave R surface plus a weak S-R attraction. The latter occurs for spacer material such as polyethylene glycol (PEG), which is weakly hydrophobic and thus attracted by protein surfaces. It is shown that the enhancement of bivalent binding can be characterized by a single key parameter, which may also provide guidelines for the design of multivalent complexes with large enhancement effect.

Molecular dynamics simulations were performed to characterize the internal motions of the ribonucleic acid apical stem loop of human hepatitis B virus. The NMR relaxation rates calculated directly from the trajectory are in good agreement with the experiment. Calculated order parameters follow the experimental pattern. Order parameters lower than 0.8 are observed for nucleotides that are weakly hydrogen bonded to their base pair partner, unpaired, or part of the loop. These residues show slow decay of the internal correlation functions of their base and sugar C-H vectors. Concerted motions around backbone dihedral angles influence the amplitude of motion of the sugar and base C-H vectors. The order parameters for base C-H vectors are also affected by the fluctuation of the glycosidic dihedral angle.

Peptide-like compounds containing an arginine have been shown to bind and stabilize the central helix of the Alzheimer's disease related amyloid-β peptide (Aβ) in an α-helical conformation, thereby delaying its aggregation into cytotoxic species. Here we study a novel Aβ targeting ligand AEDabDab containing the triamino acid, N(γ)-(2-aminoethyl)-2,4-diaminobutanoic (AEDab) acid. The new AEDab triamino acid carries an extra positive charge in the side chain and is designed to be incorporated into a ligand AEDabDab where the AEDab replaces an arginine moiety in a previously developed ligand Pep1b. This is done in order to increase the Aβ-ligand interaction, and molecular dynamics (MD) simulation of the stability of the Aβ central helix in the presence of the AEDabDab ligand shows further stabilization of the helical conformation of Aβ compared to the previously reported Pep1b as well as compared to the AEOrnDab ligand containing an N(δ)-(2-aminoethyl)-2,5-diaminopentanoic acid unit which has an additional methylene group. To evaluate the effect of the AEDabDab ligand on the Aβ neurotoxicity the AEDab triamino acid building block is synthesized by reductive alkylation of N-protected-glycinal with α-amino-protected diaminobutanoic acid, and the Aβ targeting ligand AEDabDab is prepared by solid-phase synthesis starting with attachment of glutarate to the Wang support. Replacement of the arginine residue by the AEDab triamino acid resulted in an improved capability of the ligand to prevent the Aβ1-42 induced reduction of gamma (γ) oscillations in hippocampal slice preparation.

We constructed an accurate polyether force field for implicit solvent (IS) molecular dynamics (MD) simulations that matches local and global conformations of 1,2-dimethoxy-ethane (DME) and polyethylene glycol (PEG), respectively. To make appropriate force field adjustments for IS models of PEG, we used long-term MD simulation data of 1 μs in explicit solvent (ES) based on the most recent CHARMM35 ether force field that includes adjustments for PEG in explicit water. In IS models, competition of attractive van der Waals (vdW) interactions between solute-solute and solute-solvent atom pairs is often not considered explicitly. As a consequence, the attractive vdW interactions between solute atom pairs that remain in IS models explicitly can yield equilibrium structures that are too compact. This behavior was observed in the present study comparing MD simulation data of the DME and PEG ES model with corresponding IS models that use generalized Born (GB) electrostatics combined with positive surface energy terms favoring compact structures. To regain balance of attractive vdW interactions for IS models, we considered the IS generalized Born with simple switching (GBSW) model in detail, where we turned off surface energy terms and reduced attractive vdW interactions to 90%, or we used alternatively even slightly negative surface energies. However, to obtain quantitatively the same local and global distributions of PEG conformers as in ES, we needed additional force field adjustments involving torsion potentials and 1-4 and 1-5 atom pair Coulomb interactions. This CHARMM ether force field, specifically optimized for IS simulation conditions, is equally valid for dimeric and polymeric ethylene glycol. To explore the conformational space of PEG with MD simulations, an IS GBSW model requires 2 orders of magnitude less CPU time than the corresponding ES model. About a factor of 5 of this gain in efficiency is due to the lack of solvent viscosity in IS models.