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

TL;DR

The paper explores how cryptic pockets in drug targets form through large protein conformational changes and introduces a new computational method to study these dynamics.

Contribution

A novel computational method called SLICE is introduced to guide conformational sampling for cryptic pocket discovery.

Findings

Cryptic pockets form via large conformational changes driven by disrupting local intramolecular contacts.

Perturbations like benzene probes or temperature changes failed to induce cryptic pocket formation.

The SLICE method enables efficient exploration of structural plasticity around functional protein segments.

Abstract

Allosteric pockets that typically only emerge in the
presence of
a binder, known as cryptic pockets, can provide an avenue for drug
discovery in challenging pharmaceutical targets. However, protein
conformations exposing cryptic pockets are generally short-lived and
can require significant structural rearrangements that complicate
their discovery in experiment and simulation. Here, we investigate
the structural basis of cryptic pocket formation in drug targets characterized
by extensive dynamics using simulation-based methods. We find that
functional protein segments can be anchored by local intramolecular
contacts and that disrupting these interactions drives undirected
large conformational changes to form cryptic pockets in PRMT5, PRMT6,
SMARCA2, Abl1, and PI3Kα. Perturbing the contact networks with
benzene probes, elevated temperature, or scaled protein–water
interactions could not facilitate these structural dynamics here,
indicating that complex mechanisms involving high-energy barriers
are necessary to form ligandable cryptic pockets. Based on these limitations,
a new computational approach was developed to guide conformational
sampling by local interactions surrounding functional protein segments,
termed “SLICE” (sampling by local interaction-guided
conformational exploration). Across multiple pharmaceutically relevant
proteins, our simulations aid in understanding and rapidly exploring
the large-scale structural plasticity governed by the local protein
environment around functional segments that can be leveraged for drug
discovery.

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