PROTACs are an emerging class of small molecules that induce degradation of target proteins. PROTAC typically consists of a protein-targeting ligand that is covalently linked to an E3 ligase ligand via an appropriate junction (Figure 1). By specific binding to the target protein, PROTAC recruits the E3 ligase and causes ubiquitination and subsequent degradation of the target protein via UPS. This technique has two advantages: the number of PROTAC binding sites on the same target protein may be unlimited, and the binding and degradation activity may occur on multiple target proteins, allowing for smaller drug doses and pharmacological effects to be observed.

Figure 1. Schematic diagram of the PROTAC-mediated protein degradation mechanism. (Li X, et al. 2020)

Services Items

• Molecular Dynamics Simulations

Our molecular dynamics simulations use advanced algorithms to model the interactions between PROTAC molecules, target proteins and E3 ubiquitin ligases.

We can simulate the behavior of PROTACs in different environments, including aqueous solutions and lipid membranes.

• Free energy calculations

We use free energy calculations to predict the binding affinity between PROTAC molecules and target proteins.

Our methods include thermodynamic integration, umbrella sampling, and free energy perturbation.

• Kinetic simulations

We can simulate the kinetics of PROTAC-induced protein degradation using stochastic models.

Our simulations can predict the rate and efficiency of protein degradation as a function of PROTAC concentration, target protein expression levels, and other relevant parameters.

• Ligand Design and Optimization

Using our molecular dynamics simulations and free energy calculations, we can help design and optimize PROTAC molecules to improve their binding affinity, selectivity and stability.

Solutions

• Understanding the mechanism

Our molecular dynamics simulations provide insight into the mechanism of PROTAC-induced protein degradation.

We can identify key protein-protein interactions, conformational changes and solvent effects that contribute to the efficacy of PROTACs.

• Predicting selectivity and specificity

Our free energy calculations can predict the binding affinity of PROTACs for different target proteins, enabling researchers to prioritize targets for drug development.

Technology

• Enhanced Sampling Techniques

To overcome the limitations of traditional MD simulations in sampling rare events and long timescales, we use enhanced sampling techniques such as replica exchange molecular dynamics (REMD), metadynamics, and accelerated molecular dynamics (aMD).

Why Choose Us?

PROTAC molecular dynamics services provide a powerful tool for understanding PROTAC-induced protein degradation mechanisms and optimizing ligand design. CD ComputaBio's services include molecular dynamics simulations, free energy calculations, kinetic simulations, and ligand design and optimization. Our expertise in PROTAC molecular dynamics, cutting-edge simulation methods and customized services make us an ideal partner for drug discovery and development researchers.

Reference:

1. Li X, Song Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. Journal of hematology & oncology, 2020, 13(1): 1-14.