# Decoding Allosteric Inhibition in MALT1: The Hidden Role of Conformational Plasticity in Metastable States via Biased MD and Deep Learning

## TL;DR

This paper explores how allosteric inhibition affects the MALT1 protein in mice, revealing how structural changes can block its activity, which is important for developing new cancer treatments.

## Contribution

The study introduces a novel approach combining biased MD simulations and deep learning to decode allosteric inhibition in MALT1.

## Key findings

- Loop 1 and 3 movements reduce the catalytic site cavity volume during allosteric inhibition.
- Most inhibited conformations leave the catalytic cysteine unavailable for substrate binding.
- Findings provide a computational criterion for designing new MALT1 allosteric inhibitors.

## Abstract

The mucosa-associated lymphoid tissue lymphoma-translocation
protein
1 (MALT1) is a key protein in the adaptive immune response system
in humans. This protein is widely expressed in the human body and
is related to nuclear factor-κB (NF-κB) signaling activation
in response to T-cell receptors. Due to this, MALT1 is key in the
regulation of inflammatory events in a variety of tissues, where its
dysregulation is associated with several types of cancer, especially
hematological cancers. In this sense, its relevance makes MALT1 a
valuable target to treat many diseases, drawing the attention of many
researchers with the aim of proposing new MALT1 inhibitors. However,
there is a lack of literature describing its complex dynamical behavior
and allosteric inhibition, which considerably hampers the computational
design of new MALT1 allosteric inhibitors. In that regard, the present
work investigated the complex conformational behavior of MALT1 protein
during its allosteric inhibition. For this, biased molecular dynamics
simulations, sophisticated machine learning techniques such as neural
networks, and docking calculations were used. From the performed investigation,
it was observed that through allosteric inhibition, Loop 1 and 3 movements
were crucial to reduce the catalytic site cavity volume, keeping cysteine
unavailable for substrate mimic binding. In addition, statistical
information over the explored ensemble showed that the great majority
of the inhibited conformations presented an unavailable catalytic
cysteine for substrate binding. Hence, the presented results can be
used as an objective criterion for the computational proposal of new
MALT1 allosteric inhibitors. However, despite mouse MALT1 and human
MALT1 presenting 93% homology, the generalization of the findings
to human MALT1 protein should be taken with care, and the obtained
results apply specifically to the mouse MALT1 construct.