publications

Nanomaterial Functionalization Modulates Hard Protein Corona Formation: Atomistic Simulations Applied to Graphitic Materials

Adv. Mater. Interfaces 2021, 2101236.

The protein corona is an obstacle to exploiting exotic properties of nanomaterials in clinical and biotechnological settings. The atomic-scale dynamic formation of the protein corona at the bio-nano interface is impenetrable using conventional experimental techniques. Here, molecular dynamics simulations are used to study the effect of graphene-oxide (GO) functionalization on apolipoprotein-cIII (apo-c3) adsorption. An analysis pipeline is developed, encompassing binding energy calculations to protein structure analyses employing uniform manifold approximation and projection (UMAP) dimensionality reduction and clustering. It is found that apo-c3 is denatured by GO adsorption, driven by the large energetic contributions of electrostatic interactions; enthalpic contributions of such binding events outweigh the intraprotein bond enthalpy required to maintain the protein tertiary structure. Through denaturing and exposing buried hydrophobic residues, the protein backbone is stabilized by forming β-bridges, which serve as binding motifs for protein–protein interactions that drive further protein aggregation on the nanomaterial surface. In contrast, adsorption on double-clickable azide- and alkyne-double functionalized GO (C2GO), apo-c3 largely retains its tertiary structure. Binding with the nanomaterial surface is dominated by weaker van der Waals interactions that are dispersed over the protein surface, where charged protein residues are sterically hindered by azide functional groups. The apo-c3 C-terminus remains unchanged upon C2GO adsorption, conserving its lipid-binding function.

Accurate large scale modelling of graphene oxide: ion trapping and chaotropic potential at the interface

Carbon 174 (2021): 266-275

Graphene oxide (GO) shares many novel mechanical and electronic properties with graphene and has been applied extensively for uses in physics, engineering and medicine. Computational simulations of GO have widely neglected accurate characterisation by random functionalisation, forsaking steric strain and abandoning edge functional groups. Here, we show that molecular dynamics forcefield design using electronic structure calculations of hundreds of atoms of GO with accurate functionalisation shows good agreement with state-of-the-art ab initio molecular dynamics (AIMD) simulations. We find that the bespoke forcefield shows better agreement with previous AIMD and experimental results in terms of the interfacial water dynamics and ion adsorption. Namely, GO described by the bespoke forcefield is found to disrupt the hydrogen bonding network at the interface by playing a more dynamic role in accepting and donating hydrogen bonds from water. Furthermore, with the bespoke forcefield, we find preferential adsorption of ions to carboxyl functional groups and a similar mean adsorption half-life for and ions around GO. These findings are critical for future investigations of GO in complex environments in application ranging from desalination to protein adsorption for drug delivery.

Superexchange mechanism and quantum many body excitations in the archetypal di-Cu oxo-bridge

Nature Communications Physics 3, no. 1 (2020): 1-8

The hemocyanin protein binds and transports molecular oxygen via two copper atoms at its core. The singlet state of the Cu2O2 core is thought to be stabilised by a superexchange pathway, but detailed in situ computational analysis is complicated by the multi-reference character of the electronic ground state. Here, electronic correlation effects in the functional site of hemocyanin are investigated using a novel approach, treating the localised copper 3d electrons with cluster dynamical mean field theory. This enables us to account for dynamical and multi-reference quantum mechanics, capturing valence and spin fluctuations of the 3d electrons. Our approach explains the stabilisation of the experimentally observed di-Cu singlet for the butterflied Cu2O2 core, with localised charge and incoherent scattering processes across the oxo-bridge that prevent long-lived charge excitations. This suggests that the magnetic structure of hemocyanin is largely influenced by the many-body corrections.

Allosteric Regulation of SARS-CoV-2 Protease: Towards Informed Structure-Based Drug Discovery

ChemrXiv preprint (2020)

The Coronavirus Disease of 2019 (COVID-19) is caused by a novel coronavirus known as the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research since the outset of the pandemic, definitive therapeutic agents for the treatment of the disease are yet to be identified. The main protease (MPro) of SARS-CoV-2 is an enzyme essential for virus replication through viral proteolytic activity and subsequent generation of infectious virus particles. Current computational efforts towards SARS-CoV-2 MPro inhibitor design have generally neglected an allosteric mechanism linked to His41-Cys145 catalytic dyad disruption and thus fail to target the open conformational state. We identify the rare event associated with the allosteric regulation of MPro activity in the orientation of the His41 imidazole side chain away from Cys145. In this work, we show that molecular dynamics and metadynamics simulations are fundamental for performing computer-aided MPro inhibitor design where the sampling of this allosteric mechanism within a computationally feasible timescale is essential. We calculate a 4.2 ± 1.9 kJ/mol free energy difference between the open and closed states of the SARS-CoV-2 MPro active site, indicating that favourable ligand interactions with His41 over the Cys145-His41 dyad interaction can stabilise the open state.

On the solvation of the phosphocholine headgroup in an aqueous propylene glycol solution

Journal of Chemical Physics 148, no. 13 (2018): 135102

The atomic-scale structure of the phosphocholine (PC) headgroup in 30 mol. % propylene glycol (PG) in an aqueous solution has been investigated using a combination of neutron diffraction with isotopic substitution experiments and computer simulation techniques—molecular dynamics and empirical potential structure refinement. Here, the hydration of the PC headgroup remains largely intact compared with the hydration of this group in a bilayer and in a bulk water solution, with the PG molecules showing limited interactions with the headgroup. When direct PG interactions with PC do occur, they are most likely to coordinate to the N(CH3)3+ motifs. Further, PG does not affect the bulk water structure and the addition of PC does not perturb the PG-solvent interactions. This suggests that the reason why PG is able to penetrate into membranes easily is that it does not form strong-hydrogen bonding or electrostatic interactions with the headgroup allowing it to easily move across the membrane barrier.