Low-barrier hydrogen bonds in enzyme cooperativity

Area of Science:

• Biochemistry
• Structural Biology
• Biophysics

Background:

• Protein cooperativity and allosteric regulation are key to enzyme function.
• While mechanisms are known for some proteins, the atomic basis of long-range signaling remains elusive.
• Observing mobile proton dynamics in signaling pathways is experimentally challenging.

Purpose of the Study:

• To investigate the molecular origin of long-range signaling in enzyme cooperativity.
• To experimentally observe and validate the role of hydrogen bonds in protein communication.
• To elucidate the mechanism by which catalytic events are synchronized in multimeric enzymes.

Main Methods:

• Utilized ultra-high-resolution X-ray crystallography to visualize protein structures.
• Employed computational calculations to validate experimental observations.
• Analyzed the dynamics of hydrogen bonds and proton movement within enzyme active sites.

Main Results:

• Observed fluctuating low-barrier hydrogen bonds acting as switching elements in cooperativity pathways.
• Demonstrated that these bonds, involving acidic residues and water, transmit signals via collective proton repositioning.
• Provided evidence for a 'proton Newton's cradle' mechanism synchronizing catalysis in multimeric enzymes.

Conclusions:

• Low-barrier hydrogen bonds play a crucial role in enzyme cooperativity and long-range signaling.
• This mechanism offers a new understanding of allosteric regulation at the atomic level.
• Findings suggest novel strategies for designing enzymes and drugs with enhanced regulatory capabilities.