Studi Interaksi Protein Antara Insulin Receptor Tyrosine Kinase (IRK) dan Tyrosine Phosphatase 1B (PTP1B) Dengan Metode PaCS-MD

Abstract

Resistensi insulin merupakan salah satu penyebab utama dari diabetes militus tipe 2 (T2DM) yang berkaitan erat dengan interaksi antara Protein Tyrosine Phosphatase 1B (PTP1B) dan Insulin Receptor Kinase (IRK). Penelitian ini bertujuan mempelajari interaksi kompleks PTP1B-IRK wild type dan tiga varian mutasi (p.D181E, p.D181A, p.Q262A) menggunakan metode Parallel Cascade Selection Molecular Dynamics (PaCS-MD). Dengan pendekatan ini, profil potential of mean force (PMF) diperoleh dan nilai energi bebas pengikatan dihitung dengan metode Wighted Histogram Analysis Method-Multiple Independent Umbrella Sampling (WHAM-MIUS). Hasil menunjukkan bahwa PaCS-MD secara efisien mengeksplorasi jalur disosiasi dan mampu menangkap dinamika konformasi kompleks protein dalam waktu yang relatif singkat. Mutasi p.D181E menunjukan afinitas pengikatan paling lemah, disusul p.D181A dan p.Q262A. Hasil ini menunjukan performa PaCS-MD yang baik dalam studi disosiasi protein kompleks.

Insulin resistance is one of the main causes of type 2 diabetes mellitus (T2DM) and is closely related to the interaction between Protein Tyrosine Phosphatase 1B (PTP1B) and Insulin Receptor Kinase (IRK). This study aims to investigate the interaction of the PTP1B-IRK complex in both wild-type and three mutant variants (p.D181E, p.D181A, p.Q262A) using the Parallel Cascade Selection Molecular Dynamics (PaCS-MD) method. A Potential of Mean Force (PMF) profile was obtained, and binding free energies were calculated using the Weighted Histogram Analysis Method–Multiple Independent Umbrella Sampling (WHAM-MIUS). The results show that PaCS-MD efficiently explores the dissociation pathway and captures the conformational dynamics of the protein complex in a relatively short simulation time. The p.D181E mutant exhibits the weakest binding affinity, followed by p.D181A and p.Q262A. These results indicate the good performance of PaCS-MD in protein complex dissociation studies.