Molecular Recognition in Acetylcholinesterase Catalysis: Free-Energy Correlations for Substrate Turnover and Inhibition by Trifluoro Ketone Transition-State Analogs

The key to understanding the fundamental processes of catalysis is the transition state (TS): indeed, catalysis is a transition-state molecular recognition event. Practical objectives, such as the design of TS analogues as potential drugs, or the design of synthetic catalysts (including catalytic antibodies), require prior knowledge of the TS structure to be mimicked. Examples, both old and new, of computational modelling studies are discussed, which illustrate this fundamental concept. It is shown that reactant binding is intrinsically inhibitory, and that attempts to design catalysts that focus simply upon attractive interactions in a binding site may fail. Free-energy changes along the reaction coordinate for SN2 methyl transfer catalysed by the enzyme catechol-O-methyl transferase are described and compared with those for a model reaction in water, as computed by hybrid quantum-mechanical/molecular-mechanical molecular dynamics simulations. The case is discussed of molecular recognition in a xylanase enzyme that stabilises its sugar substrate in a (normally unfavourable) boat conformation and in which a single-atom mutation affects the free-energy of activation dramatically.

Download Full-text

Understanding the Binding Transition State After the Conformational Selection Step: The Second Half of the Molecular Recognition Process Between NS1 of the 1918 Influenza Virus and Host p85β

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.716477 ◽

2021 ◽

Vol 8 ◽

Author(s):

Alyssa Dubrow ◽

Iktae Kim ◽

Elias Topo ◽

Jae-Hyun Cho

Keyword(s):

Free Energy ◽

Molecular Recognition ◽

Transition State ◽

Hydrophobic Interactions ◽

Nonstructural Protein ◽

Conformational Dynamics ◽

Linear Free Energy Relationship ◽

Conformational Selection ◽

Nonstructural Protein 1 ◽

1918 Influenza

Biomolecular recognition often involves conformational changes as a prerequisite for binding (i.e., conformational selection) or concurrently with binding (i.e., induced-fit). Recent advances in structural and kinetic approaches have enabled the detailed characterization of protein motions at atomic resolution. However, to fully understand the role of the conformational dynamics in molecular recognition, studies on the binding transition state are needed. Here, we investigate the binding transition state between nonstructural protein 1 (NS1) of the pandemic 1918 influenza A virus and the human p85β subunit of PI3K. 1918 NS1 binds to p85β via conformational selection. We present the free-energy mapping of the transition and bound states of the 1918 NS1:p85β interaction using linear free energy relationship and ϕ-value analyses. We find that the binding transition state of 1918 NS1 and p85β is structurally similar to the bound state with well-defined binding orientation and hydrophobic interactions. Our finding provides a detailed view of how protein motion contributes to the development of intermolecular interactions along the binding reaction coordinate.

Download Full-text