Molecular Mechanics Study of Flow and Surface Influence in Ligand–Protein Association

Abstract

Ligand–protein association is the first and critical step for many biological and chemical processes. This study investigated the molecular association processes under different environments. In biology, cells have different compartments where ligand–protein binding may occur on a membrane. In experiments involving ligand–protein binding, such as the surface plasmon resonance and continuous flow biosynthesis, a substrate flow and surface are required in experimental settings. As compared with a simple binding condition, which includes only the ligand, protein, and solvent, the association rate and processes may be affected by additional ligand transporting forces and other intermolecular interactions between the ligand and environmental objects. We evaluated these environmental factors by using a ligand xk263 binding to HIV protease (HIVp) with atomistic details. Using Brownian dynamics simulations, we modeled xk263 and HIVp association time and probability when a system has xk263 diffusion flux and a non-polar self-assembled monolayer surface. We also examined different protein orientations and accessible surfaces for xk263. To allow xk263 to access to the dimer interface of immobilized HIVp, we simulated the system by placing the protein 20Å above the surface because immobilizing HIVp on a surface prevented xk263 from contacting with the interface. The non-specific interactions increased the binding probability while the association time remained unchanged. When the xk263 diffusion flux increased, the effective xk263 concentration around HIVp, xk263–HIVp association time and binding probability decreased non-linearly regardless of interacting with the self-assembled monolayer surface or not. The work sheds light on the effects of the solvent flow and surface environment on ligand–protein associations and provides a perspective on experimental design.

GeomBD3: Brownian Dynamics Simulation Software for Biological and Engineered Systems

“…The biasForce keyword allows users to apply a biasing force along one dimension to mimic flow of the ligands inside the system. For example, such conditions were used to simulate surface plasmon resonance experimental conditions to investigate the effect of flow on ligand association to HIV protease . Due to the external flow effect in the system, the calculation of the rate constant using eq or is not possible.…”

“…The simulated average association time of xk263 with HIVp in the presence of SAM but no flow is 1.491 μs. The remaining association time data for each system according to flux can be found in the original research publication . With the increase in ligand flux, the concentration in the middle region of the system increases and leads to lessened ligand–surface interactions.…”

“…The software is easily capable of handling molecular models up to hundreds of nanometers in scale, thus allowing simulation of simple protein–ligand systems or very large nanoscale technologies, such as biosensors or multi-enzyme arrays. For example, the software has been used to study enzyme bioconjugates, understand DNA hybridization in biosensors, and replicate SPR experiments under diffusive flux . Users may also arrange multiple enzymes in space or on a membrane to study ligand diffusion in crowded environments.…”

Brownian dynamics simulations of biomolecular diffusional association processes

“…Another BD study of HIV‐1 protease, focused on the association of its inhibitor, xk263 in a surface plasmon resonance or continuous flow biosynthesis experimental environment which was mimicked by a model self‐assembled monolayer surface and a simulated current flux of xk263 98 . The BD simulations allowed the effects of different fluxes and different protein orientations and interactions on the protease–inhibitor association times to be investigated, showing how such simulations could guide experimental design.…”

Recognition of quinolone antibiotics by the multidrug efflux transporter MexB ofPseudomonas aeruginosa

“…Molecular recognition between protein and ligand complexes is driven by inter-molecular forces and shape complementarity. 1 In the case of non-covalent bonds, binding can have either a polar (electrostatic interactions and hydrogen bonds) or an apolar (van der Waals and hydrophobic interactions) characteristic. 2 In general, the higher the complementarity between polar and apolar surfaces, the higher the affinity of a compound to a protein target.…”