Effect of a Low Electrostatic Environment on the Helical Structures of Peptides and Proteins Using Flexible Water Models: An In Silico Study

TL;DR

This study explores how low electrostatic water models affect the structure of membrane proteins and peptides, showing improved stability and interactions.

Contribution

The paper introduces new flexible water models that simulate low dielectric environments to better understand membrane protein behavior.

Findings

Low electrostatic water models increase hydrogen bonding and structural stability in peptides and membrane proteins.

These models enhance interactions between transmembrane domains, preventing structural deformation.

Improved membrane properties like thickness and diffusion were observed with low electrostatic solvents.

Abstract

The electrostatic
representation of the molecular environment
surrounding
membrane proteins is a topic that has not been addressed in the field
of molecular simulations. The forces produced by such environments
play a decisive role in processes such as GPCR activation, molecular
recognition between membrane components, and interactions with ligands,
directly impacting their dynamics and physiological function. Based
on the FBA/ϵ and TIP4P/ϵflex parameters, we
have constructed two new flexible water models to produce low dielectric
constants in order to study their effect on the structural properties
of protein–membrane complexes. These new low electrostatic
water (LEw) models were tested on five helical peptides and two helical-type
integral membrane proteins (IMPs) by using molecular dynamics simulations
and other in silico tools. Our results show that
LEw models enhance intramolecular interactions by producing more hydrogen
bonds within the protein structures, leading to greater compaction
and conservation of their secondary structures. In the case of IMPs,
a low electrostatic solvent leads to greater interaction between the
transmembrane domains, preventing their opening and structural deformation.
Furthermore, although these models increased their interactions with
the membrane, an improvement in properties such as thickness, area
per lipid, and lateral diffusion was observed. These novel models
would enable for a more accurate description and understanding of
the various interactions between membrane proteins, potentially leading
to the development of more effective drugs targeting these therapeutic
targets. Furthermore, this new approach could be applied in the study
of more complex membrane models. This work highlights the importance
of developing new water models that improve the molecular description
of the environment surrounding cell membranes and enable us to generate
more reliable computer results.

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