ArticleBiophysical journal2008
Ligand escape pathways and (un)binding free energy calculations for the hexameric insulin-phenol complex.
Article in Biophysical journal, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 78 citations in OpenAlex.
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- Enzymatic-related network of catalysis, polyamine, and tumors for acetylpolyamine oxidase: from calculation to experiment.Chemical science · 2024Article
- Progress in Simulation Studies of Insulin Structure and Function.Frontiers in endocrinology · 2022Review
- Role of salt-bridging interactions in recognition of viral RNA by arginine-rich peptides.Biophysical journal · 2021Article
- Kinetics of Phenol Escape from the Insulin RThe journal of physical chemistry. B · 2021Article
- Atomic-Level Investigation of Reactant Recognition Mechanism and Thermodynamic Property in Glucosamine 6-Phosphate Deaminase Catalysis.Frontiers in chemistry · 2021Article
- Combination of multiple computational methods revealing specific sub-sectional recognition and hydrogen-bond dependent transportation of CKII peptide fragment in O-GlcNAc transferase.Computational and structural biotechnology journal · 2021Article
- Calculating the absolute binding free energy of the insulin dimer in an explicit solvent.RSC advances · 2020Article
- Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase.Frontiers in chemistry · 2020Article
- Structural Analysis ofFrontiers in bioengineering and biotechnology · 2019Article
- The GluN2B-Glu413Gly NMDA receptor variant arising from a de novo GRIN2B mutation promotes ligand-unbinding and domain opening.Proteins · 2018Article
- Detailed potential of mean force studies on host-guest systems from the SAMPL6 challenge.Journal of computer-aided molecular design · 2018Article
- Human hydroxymethylbilane synthase: Molecular dynamics of the pyrrole chain elongation identifies step-specific residues that cause AIP.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Study on the Application of the Combination of TMD Simulation and Umbrella Sampling in PMF Calculation for Molecular Conformational Transitions.International journal of molecular sciences · 2016Article
- Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design.Biochimica et biophysica acta · 2016Article
- Extracting ligands from receptors by reversed targeted molecular dynamics.Journal of computer-aided molecular design · 2015Article
- A Self-Adaptive Steered Molecular Dynamics Method Based on Minimization of Stretching Force Reveals the Binding Affinity of Protein-Ligand Complexes.Molecules (Basel, Switzerland) · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cooperative binding of phenolic species to insulin hexamers is known to stabilize pharmaceutical preparations of the hormone. Phenol dissociation is rapid on hexamer dissolution timescales, and phenol unbinding upon dilution is likely the first step in the conversion of (pharmaceutical) hexameric insulin to the active monomeric form upon injection. However, a clear understanding of the determinants of the rates of phenol unbinding remains obscure, chiefly because residues implicated in phenol exchange as determined by NMR are not all associated with likely unbinding routes suggested by the best-resolved hexamer structures. We apply random acceleration molecular dynamics simulation to identify potential escape routes of phenol from hydrophobic cavities in the hexameric insulin-phenol complex. We find three major pathways, which provide new insights into (un)binding mechanisms for phenol. We identify several residues directly participating in escape events that serve to resolve ambiguities from recent NMR experiments. Reaction coordinates for dissociation of phenol are developed based on these exit pathways. Potentials of mean force along the reaction coordinate for each pathway are resolved using multiple independent steered molecular dynamics simulations with second-order cumulant expansion of Jarzynski's equality. Our results for DeltaF agree reasonably well within the range of known experimental and previous simulation magnitudes of this quantity. Based on structural analysis and energetic barriers for each pathway, we suggest a plausible preferred mechanism of phenolic exchange that differs from previous mechanisms. Several weakly-bound metastable states are also observed for the first time in the phenol dissociation reaction.
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