scholarly journals Allosteric signalling paths in hemoglobin: a protein dynamics network analysis

2017 ◽  
Author(s):  
Emanuele Monza ◽  
George Blouin ◽  
Thomas G. Spiro ◽  
Victor Guallar
Keyword(s):  
Molecular Dynamics ◽  
Network Analysis ◽  
Ligand Binding ◽  
Protein Dynamics ◽  
Oxygen Binding ◽  
Subunit Interactions ◽  
Protein Fragments ◽  
Allosteric Communication ◽  
Dynamics Simulations ◽  
Signalling Process

AbstractHemoglobin is the paradigm of cooperative protein-ligand binding. Cooperativity is the consequence of inter-subunit allosteric communication: binding at one site increases the affinity of the others. Despite half a century of studies, the mechanism behind oxygen binding in hemoglobin is not fully understood yet. In particular, it is not clear if cooperativity arises from preferential inter-subunit channels and which residues propagate the allosteric signal from one heme to the others. In this work, the heme-heme dynamical interactions have been mapped through a network-based analysis of residue conformational fluctuations, as described by molecular dynamics simulations. In particular, it was possible to suggest which inter-subunit interactions are mostly responsible of allosteric signalling and, within each pair of subunits, which protein fragments convey such signalling process.

scholarly journals The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1250
Author(s):  
Hien T. T. Lai ◽  
Alejandro Giorgetti ◽  
Giulia Rossetti ◽  
Toan T. Nguyen ◽  
Paolo Carloni ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Transmembrane Protein ◽  
Free Form ◽  
Experimental Investigations ◽  
Terminal Part ◽  
Dynamics Simulations ◽  
Cholesterol Binding

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol–binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N–terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C–terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150–X–Y152–X(3)–R156 and R135–X(2)–Y138–X(2)–L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC–resembling motif that we observed in TM I (residues L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We expect that the CRAC–like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.

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