Electronic polarization effects on membrane translocation of anti-cancer drugs.

Free-energy calculations are crucial for investigating biomolecular interactions. However, in theoretical studies, the neglect of electronic polarization can reduce predictive capabilities, specifically for free-energy calculations. To effectively mimick polarization, we explore a Charge Switching (CS) model, aiming to narrow the gap between computational and experimental results. The model requires quantum-level partial charge calculations of the molecule in different environments, combined with atomistic MD simulations. Studying three different anti-cancer drug molecules with three different phospholipid membranes, we show that the method significantly improves agreement with available experimental data. In contrast, using conventional fixed charge atomistic methods, qualitative discrepancies with experiments are observed, and we show that neglecting polarization may lead to an unphysical free energy sign inversion. While the CS method is here applied to anti-cancer drug-membrane translocation, it could be used more generally to study processes considering solvent effects.

A modified Jarzynski free-energy estimator to eliminate non-conservative forces and its application in nanoparticle-membrane interactions.

Computational methods to understand interactions in bio-complex systems are however limited to time-scales typically much shorter than in Nature. For example, on the nanoscale level, interactions between nanoparticles (NPs)/molecules/peptides and membranes are central in complex biomolecular processes such as membrane-coated NPs or cellular uptake. This can be remedied by the application of e.g. Jarzynski's equality where thermodynamic properties are extracted from non-equilibrium simulations. Although, the out of equilibrium work leads to non-conservative forces. We here propose a correction Pair Forces method, that removes these forces. Our proposed method is based on the calculation of pulling forces in backward and forward directions for the Jarzynski free-energy estimator using steered molecular dynamics simulation. Our results show that this leads to much improvement for NP-membrane translocation free energies. Although here we have demonstrated the application of the method in molecular dynamics simulation, it could be applied for experimental approaches.

Conformation- and phosphorylation-dependent electron tunnelling across self-assembled monolayers of tau peptides.

We report on charge transport across self-assembled monolayers (SAMs) of short tau peptides by probing the electron tunneling rates and quantum mechanical simulation. We measured the electron tunneling rates across SAMs of carboxyl-terminated linker molecules (C6H12O2S) and short cis-tau (CT) and trans-tau (TT) peptides, supported on template-stripped gold (AuTS) bottom electrode, with Eutectic Gallium-Indium (EGaIn)(EGaIn) top electrode. Measurements of the current density across thousands of AuTS/linker/tau//Ga2O3/EGaIn single-molecule junctions show that the tunneling current across CT peptide is one order of magnitude lower than that of TT peptide. Quantum mechanical simulation demonstrated a wider energy bandgap of the CT peptide, as compared to the TT peptide, which causes a reduction in its electron tunneling current. Our findings also revealed the critical role of phosphorylation in altering the charge transport characteristics of short peptides; more specifically, we found that the presence of phosphate groups can reduce the energy band gap in tau peptides and alter their electrical properties. Our results suggest that conformational and phosphorylation of short peptides (e.g., tau) can significantly change their charge transport characteristics and energy levels.

Mechanistic Understanding of the Interactions between Nano-Objects with Different Surface Properties and α-Synuclein.

Aggregation of the natively unfolded protein α-synuclein (α-syn) is key to the development of Parkinson's disease (PD). Some nanoparticles (NPs) can inhibit this process and in turn be used for treatment of PD. Using simulation strategies, we show here that α-syn self-assembly is electrostatically driven. Dimerization by head-to-head monomer contact is triggered by dipole-dipole interactions and subsequently stabilized by van der Waals interactions and hydrogen bonds. Therefore, we hypothesized that charged nano-objects could interfere with this process and thus prevent α-syn fibrillation. In our simulations, positively and negatively charged graphene sheets or superparamagnetic iron oxide NPs first interacted with α-syn's N/C terminally charged residues and then with hydrophobic residues in the non-amyloid-ß component (61-95) region. In the experimental setup, we demonstrated that the charged nano-objects have the capacity not only to strongly inhibit α-syn fibrillation (both nucleation and elongation) but also to disaggregate the mature fibrils. Through the α-syn fibrillation process, the charged nano-objects induced the formation of off-pathway oligomers.

Molecular interaction of fibrinogen with zeolite nanoparticles.

Fibrinogen is one of the key proteins that participate in the protein corona composition of many types of nanoparticles (NPs), and its conformational changes are crucial for activation of immune systems. Recently, we demonstrated that the fibrinogen highly contributed in the protein corona composition at the surface of zeolite nanoparticles. Therefore, understanding the interaction of fibrinogen with zeolite nanoparticles in more details could shed light of their safe applications in medicine. Thus, we probed the molecular interactions between fibrinogen and zeolite nanoparticles using both experimental and simulation approaches. The results indicated that fibrinogen has a strong and thermodynamically favorable interaction with zeolite nanoparticles in a non-cooperative manner. Additionally, fibrinogen experienced a substantial conformational change in the presence of zeolite nanoparticles through a concentration-dependent manner. Simulation results showed that both E- and D-domain of fibrinogen are bound to the EMT zeolite NPs via strong electrostatic interactions, and undergo structural changes leading to exposing normally buried sequences. D-domain has more contribution in this interaction and the C-terminus of γ chain (γ377-394), located in D-domain, showed the highest level of exposure compared to other sequences/residues.