Dynamut Omicron Mpro with P132H mutation


Analysis and prediction of protein stability changes upon mutation using Normal Mode Analysis


Proteins are highly dynamic molecules, whose function is intrinsically linked to their molecular motions. Despite the pivotal role of protein dynamics, their computational simulation cost has led to most structure-based approaches for assessing the impact of mutations on protein structure and function relying upon static structures. Here we present DynaMut, a web server implementing two distinct, well established normal mode approaches, which can be used to analyze and visualize protein dynamics by sampling conformations and assess the impact of mutations on protein dynamics and stability resulting from vibrational entropy changes. DynaMut integrates our graph-based signatures along with normal mode dynamics to generate a consensus prediction of the impact of a mutation on protein stability. We demonstrate our approach outperforms alternative approaches to predict the effects of mutations on protein stability and flexibility (P-value < 0.001), achieving a correlation of up to 0.70 on blind tests. DynaMut also provides a comprehensive suite for protein motion and flexibility analysis and visualization via a freely available, user friendly web server at http://biosig.unimelb.edu.au/dynamut/.

Omicron Mpro with P132H mutation

Δ Vibrational Entropy Energy Between Wild-Type and Mutant ΔΔSVib ENCoM: -0.874 kcal.mol-1.K-1 (Decrease of molecule flexibility)


Amino acids colored according to the vibrational entropy change upon mutation. BLUE represents a rigidification of the structure and RED a gain in flexibility.

The mutation P132H is situated in a cleft between domains II and III. This region is, according to the prediction, rigidified. Two of the five antiparallel α-helices of domain III seems to be the most impacted by this rigidification.

The active site and the catalytic dyad, situated at the split between domain I and II, does not seem to be affected.

The C- and N-terminus of the monomers constitute the dimer interface and seem not to be impacted by the mutation.

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