Investigation of selective binding of inhibitors to PTP1B and TCPTP by accelerated molecular dynamics simulations

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology
• Computational Biology

Background:

• Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of insulin signaling, making it a therapeutic target for type II diabetes and obesity.
• The selectivity of PTP1B inhibitors against T-cell protein tyrosine phosphatase (TCPTP) is poorly understood due to high sequence similarity and lack of TCPTP complex structures.

Purpose of the Study:

• To investigate the structural dynamics of PTP1B and TCPTP complexes with chemically similar inhibitors exhibiting distinct selectivity.
• To elucidate the molecular mechanisms governing inhibitor selectivity between PTP1B and TCPTP.

Main Methods:

• Accelerated molecular dynamics (aMD) simulations to capture conformational transitions.
• Free energy profile analysis of key residue interactions.
• Molecular mechanics with the Poisson-Boltzmann and surface area solvation (MM-PBSA) calculations.
• Alanine scanning mutagenesis to assess residue contributions.

Main Results:

• Conformational transitions between 'open' and 'closed' states were observed for four inhibitor-protein complexes.
• Distinct conformational behaviors of the WPD-loop, R-loop, and second pTyr binding site were identified and linked to inhibitor selectivity.
• MM-PBSA calculations and mutagenesis validated the binding free energies and identified critical residues.

Conclusions:

• Inhibitor-induced conformational changes in specific loops and binding sites are crucial for achieving selectivity between PTP1B and TCPTP.
• These findings provide mechanistic insights for the rational design of more specific PTP1B inhibitors for therapeutic applications.