The Role of the Electronic Structure during Protein Folding through Electron Density-Based Quantum Chemical Descriptors

TL;DR

This paper explores how the electronic structure of proteins influences their folding process using quantum chemical descriptors.

Contribution

The study introduces a novel analysis of local hardness fluctuations during protein folding, revealing electronic structure signatures.

Findings

Local hardness per residue (ηj) fluctuates around native values during folding rather than monotonically changing.

ηj stabilizes as the protein reaches its folded state, distinguishing native from non-native structures.

Electronic structure plays a significant role in the folding process, as shown by ηj behavior.

Abstract

One of the major challenges in protein folding is understanding
the role that the electronic structure of proteins plays during their
folding. We emphasize that the structural and dynamic properties of
proteins are extremely important for understanding how their conformational
changes occur during folding. However, since the electronic structure
is intrinsically related to the atomic structure, further analysis
of the electronic structure during folding may assist in the development
of methods for predicting protein biological activity. In this study,
we applied statistical sampling in molecular dynamics folding trajectories,
and subsequent calculations of global and local quantum chemical molecular
descriptors calculated by DFT-D3 and semiempirical quantum chemical
methods for three fast-folding proteins (NTL9, BBA, and α3D).
We observe an intriguing trend in the local hardness per residue (η
j
). Specifically, soft residues do not become
softer as the trajectory progresses until they reach the expected
softness, and hard residues do not become progressively harder. Rather,
a subtle process occurs in which the local hardness fluctuates above
and below the final native values for each residue. The point is not
that the folded structures have more favorable hard or soft interactions
in their residues, but that η
j
becomes
stable as the conformation approaches the folded state. In addition,
we observed that η
j
can distinguish
non-native from native-like structures, revealing that intrinsic aspects
of the electronic structure play a highly relevant role in the protein
folding process. These observations could show an electronic structure
signature during protein folding.

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