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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.

SUBMITTER: Kaushik S

PROVIDER: S-EPMC8142692 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Conventional macromolecular crystallographic refinement relies on often dubious stereochemical restraints, the preparation of which often requires human validation for unusual species, and on rudimentary energy functionals that are devoid of nonbonding effects owing to electrostatics, polarization, charge transfer or even hydrogen bonding. While this approach has served the crystallographic community for decades, as structure-based drug design/discovery (SBDD) has grown in prominence it has become clear that these conventional methods are less rigorous than they need to be in order to produce properly predictive protein-ligand models, and that the human intervention that is required to successfully treat ligands and other unusual chemistries found in SBDD often precludes high-throughput, automated refinement. Recently, plugins to the Python-based Hierarchical ENvironment for Integrated Xtallography (PHENIX) crystallographic platform have been developed to augment conventional methods with the in situ use of quantum mechanics (QM) applied to ligand(s) along with the surrounding active site(s) at each step of refinement [Borbulevych et al. (2014), Acta Cryst D70, 1233-1247]. This method (Region-QM) significantly increases the accuracy of the X-ray refinement process, and this approach is now used, coupled with experimental density, to accurately determine protonation states, binding modes, ring-flip states, water positions and so on. In the present work, this approach is expanded to include a more rigorous treatment of the entire structure, including the ligand(s), the associated active site(s) and the entire protein, using a fully automated, mixed quantum-mechanics/molecular-mechanics (QM/MM) Hamiltonian recently implemented in the DivCon package. This approach was validated through the automatic treatment of a population of 80 protein-ligand structures chosen from the Astex Diverse Set. Across the entire population, this method results in an average 3.5-fold reduction in ligand strain and a 4.5-fold improvement in MolProbity clashscore, as well as improvements in Ramachandran and rotamer outlier analyses. Overall, these results demonstrate that the use of a structure-wide QM/MM Hamiltonian exhibits improvements in the local structural chemistry of the ligand similar to Region-QM refinement but with significant improvements in the overall structure beyond the active site.

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

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