J. G. Vilhena

Albumin (BSA) Adsorption over Graphene in Aqueous Environment: Influence of Orientation, Adsorption Protocol, and Solvent Treatment.

We report 150 ns explicit solvent MD simulations of the adsorption on graphene of albumin (BSA) in two orientations and using two different adsorption protocols, i.e., free and forced adsorption. Our results show that free adsorption occurs with little structural rearrangements. Even taking adsorption to an extreme, by forcing it with a 5 nN downward force applied during the initial 20 ns, we show that along a particular orientation BSA is able to preserve the structural properties of the majority of its binding sites. Furthermore, in all the cases considered in this work, the ibuprofen binding site has shown a strong resilience to structural changes. Finally, we compare these results with implicit solvent simulations and find that the latter predicts an extreme protein unfolding upon adsorption. The origin of this discrepancy is attributed to a poor description of the water entropic forces at interfaces in the implicit solvent methods.

Atomic-Scale Sliding Friction on Graphene in Water.

The sliding of a sharp nanotip on graphene completely immersed in water is investigated by molecular dynamics (MD) and atomic force microscopy. MD simulations predict that the atomic-scale stick-slip is almost identical to that found in ultrahigh vacuum. Furthermore, they show that water plays a purely stochastic role in sliding (solid-to-solid) friction. These observations are substantiated by friction measurements on graphene grown on Cu and Ni, where, oppositely of the operation in air, lattice resolution is readily achieved. Our results promote friction force microscopy in water as a robust alternative to ultra-high-vacuum measurements.

Understanding the mechanical response of double-stranded DNA and RNA under constant stretching forces using all-atom molecular dynamics

Significance The mechanical properties of nucleic acids regulate multiple biological processes ranging from complex chromosome packing to replication of a plasmid. Single-molecule experiments have reported puzzling differences between the mechanical properties of double-stranded DNA (dsDNA) and double-stranded RNA (dsRNA) subjected to force and torque. This study investigates these differences using constant-force, all-atom, microsecond-long molecular dynamics. We provide a physical mechanism that explains the nonintuitive opposite twist-stretch response of these molecules based on the change of the interstrand distance with the stretching force. Changes in interstrand distance are ultimately related to differences in the chemical structure of dsDNA and dsRNA molecules. The methodology and results shown here open the field to explore larger forces to test experimental measurements, and to challenge the predictions given by our simulations. Multiple biological processes involve the stretching of nucleic acids (NAs). Stretching forces induce local changes in the molecule structure, inhibiting or promoting the binding of proteins, which ultimately affects their functionality. Understanding how a force induces changes in the structure of NAs at the atomic level is a challenge. Here, we use all-atom, microsecond-long molecular dynamics to simulate the structure of dsDNA and dsRNA subjected to stretching forces up to 20 pN. We determine all of the elastic constants of dsDNA and dsRNA and provide an explanation for three striking differences in the mechanical response of these two molecules: the threefold softer stretching constant obtained for dsRNA, the opposite twist-stretch coupling, and its nontrivial force dependence. The lower dsRNA stretching resistance is linked to its more open structure, whereas the opposite twist-stretch coupling of both molecules is due to the very different evolution of molecules’ interstrand distance with the stretching force. A reduction of this distance leads to overwinding in dsDNA. In contrast, dsRNA is not able to reduce its interstrand distance and can only elongate by unwinding. Interstrand distance is directly correlated with the slide base-pair parameter and its different behavior in dsDNA and dsRNA traced down to changes in the sugar pucker angle of these NAs.

DNA crookedness regulates DNA mechanical properties at short length scales

Sequence-dependent DNA conformation and flexibility play a fundamental role in specificity of DNA-protein interactions. Here we quantify the DNA crookedness: a sequence-dependent deformation of DNA that consists on periodic bends of the base pair centers chain. Using molecular dynamics simulations, we found that DNA crookedness and its associated flexibility are bijective: unveiling a one-to-one relation between DNA structure and dynamics. This allowed us to build a predictive model to compute DNA stretching stiffness from solely its structure. Sequences with very little crookedness show extremely high stiffness and have been previously shown to form unstable nucleosomes and promote gene expression. Interestingly, the crookedness can be tailored by epigenetic modifications, known to affect gene expression. Our results rationalize the idea that the DNA sequence is not only a chemical code, but also a physical one that allows to finely regulate its mechanical properties and, possibly, its 3D arrangement inside the cell.

Stick–Slip Motion of ssDNA over Graphene

We have performed molecular dynamics simulations of nanomanipulation experiments on short single-stranded DNA chains elastically driven on a graphene surface. After a brief transient, reproducible stick-slip cycles are observed on chains made by 10 units of thymine, cytosine, adenine, and guanine. The cycles have the periodicity of the graphene substrate, and take place via an intermediate stage, appearing as a dip in the sawtooth variations of lateral force recorded while the chains are manipulated. Guanine presents remarkable differences from the other bases, since a lower number of nucleotides are prone to stick to the substrate in this case. Nevertheless, the magnitudes of static friction and lateral stiffness are similar for all chains (30 pN and 0.7 N/m per adsorbed nucleotide respectively).

Albumin (BSA) adsorption onto graphite stepped surfaces

Nanomaterials are good candidates for the design of novel components with biomedical applications. For example, nano-patterned substrates may be used to immobilize protein molecules in order to integrate them in biosensing units. Here, we perform long MD simulations (up to 200 ns) using an explicit solvent and physiological ion concentrations to characterize the adsorption of bovine serum albumin (BSA) onto a nano-patterned graphite substrate. We have studied the effect of the orientation and step size on the protein adsorption and final conformation. Our results show that the protein is stable, with small changes in the protein secondary structure that are confined to the contact area and reveal the influence of nano-structuring on the spontaneous adsorption, protein-surface binding energies, and protein mobility. Although van der Waals (vdW) interactions play a dominant role, our simulations reveal the important role played by the hydrophobic lipid-binding sites of the BSA molecule in the adsorption process. The complex structure of these sites, that incorporate residues with different hydrophobic character, and their flexibility are crucial to understand the influence of the ion concentration and protein orientation in the different steps of the adsorption process. Our study provides useful information for the molecular engineering of components that require the immobilization of biomolecules and the preservation of their biological activity.