Fatty Acid and Retinol-Binding Protein: Unusual Protein Conformational and Cavity Changes Dictated by Ligand Fluctuations

Abstract

Lipid-binding proteins (LBPs) are soluble proteins responsible for the uptake, transport, and storage of a large variety of hydrophobic lipophilic molecules including fatty acids, steroids, and other lipids in the cellular environment. Among the LBPs, fatty acid binding proteins (FABPs) present preferential binding affinities for long-chain fatty acids. While most of FABPs in vertebrates and invertebrates present similar β-barrel structures with ligands accommodated in their central cavity, parasitic nematode worms exhibit additional unusual α-helix rich fatty acid-and retinol-binding proteins (FAR). Herein, we report the comparison of extended molecular dynamics (MD) simulations performed on the ligand-free and palmitic acid-bond states of the Necator americanus FAR-1 (Na-FAR-1) with respect to other classical β-barrel FABPs. Principal component analysis (PCA) has been used to identify the different conformations adopted by each system during MD simulations. The αhelix fold encompasses a complex internal ligand-binding cavity with a remarkable conformational plasticity that allows reversible switching between distinct states in the holo-Na-FAR-1. The cavity can change up to one-third of its size affected by conformational changes of the protein−ligand complex. Besides, the ligand inside the cavity is not fixed but experiences large conformational changes between bent and stretched conformations. These changes in the ligand conformation follow changes in the cavity size dictated by the transient protein conformation. On the contrary, protein−ligand complex in β-barrel FABPs fluctuates around a unique conformation. The significantly more flexible holo-Na-FAR-1 ligand-cavity explains its larger ligand multiplicity respect to β-barrel FABPs. 38 perform very important functions for parasite growth and 39 development. 40 Fatty acid and retinol binding proteins (FARs) are LBPs that 41 have been described as components of E/S fluids from 42 parasitic nematodes 4−7 and they are hypothesized to play 43 essential roles in lipid acquisition and distribution of nutrients 44 as well as potential dampening of host's immune response. 8,9 45 FARs together with nematode polyprotein/allergens (NPAs) 10 46 are small (14−20 kDa), helix rich proteins that bind retinol 47 and fatty acids and have no recognizable counterparts in other 48 animal groups. 2 Given these characteristics, FARs have been 49 proven to be useful for serodiagnosis and experimental

From Data to Knowledge: Systematic Review of Tools for Automatic Analysis of Molecular Dynamics Output

“…Dimensionality reduction of MD data with the use of PCA was also first used in the early 90s ( Ichiye and Karplus, 1991 ; Amadei et al, 1993 ) and since that time its application in MD output analysis has been constantly growing ( Das and Mukhopadhyay, 2007 ; Chiappori et al, 2010 ; Kim et al, 2010 ; Casoni et al, 2013 ; Ng et al, 2013 ; Novikov et al, 2013 ; Bhakat et al, 2014 ; Sittel et al, 2014 ; Ernst et al, 2015 ; Chaturvedi et al, 2017 ; Cossio-Pérez et al, 2017 ; Fakhar et al, 2017 ; Chen, 2018 ; Cholko et al, 2018 ; An et al, 2019 ; Barletta et al, 2019 ; Girdhar et al, 2019 ; Karnati and Wang, 2019 ; Lipiński et al, 2019 ; Martínez-Archundia et al, 2019 ; Wu et al, 2019 ; Magudeeswaran and Poomani, 2020 ; David et al, 2021 ; Majumder and Giri, 2021 ). Although PCA is the most popular approach applied to handle MD trajectories, other data dimensionality reduction methods are also used in the MD field.…”

Interaction of the new inhibitor paxlovid (PF-07321332) and ivermectin with the monomer of the main protease SARS-CoV-2: A volumetric study based on molecular dynamics, elastic networks, classical thermodynamics and SPT

“…The partial molar volume of protein by definition ( Awoonor-Williams and Abu-Saleh, 2021 , Azam et al, 2021 , Fornés, 2008 , González-Paz et al, 2022 , Jofily et al, 2021 ) is considered to be constituted of two volumetric contributions, a molecular or geometric contribution (volume of van der Waals and volume of internal voids ) and a non-intrinsic contribution (volumetric contribution from repulsive and attractive interactions ): is the van der Waals volumes of all the protein constitutive atoms of protein and is volume of cavities within the protein from imperfect atomic packing, dependent of temperature, proportional to molar mass , and equal to the geometric volume of protein impenetrable to surrounding solvent molecules ( Azam et al, 2021 , Azam et al, 2020 , Ball, 2017 , Barletta and Fernández-Alberti, 2018 , Barletta et al, 2019 , Brovchenko et al, 2010 , Fleming and Fleming, 2018 , González-Paz et al, 2021 ). While the thermal volume (by definition is a quantity positive, i,e, ) is the empty volume around of protein which is due to the mutual protein-solvent vibrations, intermolec...…”

“…As some authors ( Alvarado et al, 2018 , Alvarado et al, 2015 , Alvarado et al, 2021 ) have conclusively demonstrated, this type of study provides information on the role played by hydration in modulating protein stability and its role in ligand binding reactions. It is important to mention that it has been shown that protein-protein and protein-ligand interactions occur with the loss or gain of water molecules around the ligand and/or protein (biological water), a phenomenon with potential pharmacological impact because it is key to the biological activity of these proteins ( Antonopoulou et al, 2022 , Awoonor-Williams and Abu-Saleh, 2021 , Azam et al, 2021 , Azam et al, 2020 , Ball, 2017 , Barletta and Fernández-Alberti, 2018 , Barletta et al, 2019 , Blake and Soliman, 2014 , Brovchenko et al, 2010 ). Despite the theoretical effort made and the in vitro studies of its antiviral activity to date, there are still no experimental reports that confirm the binding and perturbation of M pro by ivermectin.…”

Analysis of changes of cavity volumes in predefined directions of protein motions and cavity flexibility

“…These subunits not only act as essential components of the dynein motor complex, but also regulate a large variety of biological events by binding to numerous proteins and enzymes. 62,[64][65][66] DLC8 and TcTex1 present two flexible peptide-binding clefts to achieve binding specificity (see Figures 5A and 6A).…”