Exploring the Structural Basis of Cryptic Pocket Formation Driven by Extensive Protein Conformational Changes in Drug...

Area of Science:

• Biochemistry
• Computational Biology
• Drug Discovery

Background:

• Cryptic pockets are transient allosteric binding sites crucial for drug discovery.
• Their formation involves significant protein conformational changes, posing challenges for experimental and computational identification.
• Understanding the dynamics of these pockets is key to targeting challenging pharmaceutical proteins.

Purpose of the Study:

• Investigate the structural basis of cryptic pocket formation in dynamic drug targets.
• Identify mechanisms driving the exposure of cryptic pockets.
• Develop a computational strategy to facilitate the exploration of cryptic pockets.

Main Methods:

• Utilized simulation-based methods to study cryptic pocket formation in PRMT5, PRMT6, SMARCA2, Abl1, and PI3Kα.
• Analyzed the role of local intramolecular contacts in anchoring functional protein segments.
• Developed and applied the SLICE (sampling by local interaction-guided conformational exploration) computational approach.

Main Results:

• Disruption of local intramolecular contacts drives large conformational changes leading to cryptic pocket formation.
• Simple perturbations like benzene probes or altered solvent interactions were insufficient to induce pocket formation.
• The SLICE method effectively guided conformational sampling around functional segments.
• The study revealed that high-energy barriers are involved in forming ligandable cryptic pockets.

Conclusions:

• Cryptic pocket formation is governed by complex mechanisms and high-energy barriers, not easily overcome by simple perturbations.
• The SLICE computational approach enhances the understanding and exploration of protein structural plasticity.
• This method facilitates the discovery of novel drug targets by leveraging the dynamics of functional protein segments.