Molecular Dynamics Simulation of human Aquaporin 1: influences on water pathway of Loop A and Ca restrains

ROSI, PABLO; COSTA ALMAR, FLORENCIA; MIRANDA, LUCAS; OZU, MARCELO; DORR, RICARDO; TORIANO, ROXANA

Buenos Aires

Congreso; Latin American Conference on Mathematical Modeling of Biological Systems - Encuentros, desencuentros y reencuentros entre la matemática aplicada y la biofísica experimental; 2015

La Sociedad Argentina de Biofísica (SAB) y el Centro Latinoamerica de Formación Interdisciplinaria (CELFI)

The Aquaporins (AQPs) are a family of tetrameric membrane integral proteinswhich facilitate water transport across the cell membrane. Each monomer ofAQPs contains a water channel. Our former in vitro results showed thathuman AQP1 (hAQP1) is regulated by increments in membrane-tensioncaused by osmotic gradient1 or by co-expression of ENaC. Our present goalwas to study conformational changes in hAQP1 structure as a putativephysiological way to modify water permeability in cells. In silico experimentswere performed by Molecular Dynamics Simulations (MDS), using PDBtemplates of two hAQP1 structures deposited in Protein Data Bank undercodes 1FQY and 4CSK: 3.8 Å resolution 1FQY structure solved by electroncrystallography containing 269 residues2 and 3.28 Å resolution 4CSKstructured solved by X-ray diffraction containing 292 residues3. MDSexperiments (50ns in explicit aqueous solvent) were carried out under twodifferent conditions: unrestricted and restricted α-Carbon. In this latter one,only α-Carbons in the lipophilic region of the monomers were fixed thus thiscondition resembles the anchoring of the protein in the cellular membrane.Both the isolated monomer and the monomer inside the tetramers werestudied. To analyze the water channel profile along dynamic experiments weused the PoreWalker server. Loop A flexibility was assessed in order toevaluate the possible interaction with the vestibule of the neighbour monomer,this one was evaluated by g(r) function and its integral. Furthermore distancesbetween specific NPA residues were considered.Conclusions: The tetrameric conformation maintains the structure andfunctionality of each monomer which might have an independent behaviorregarding water movement. Environmental influences can causeconformational changes that might modulate water permeability eventhoughAQP1 was described as a constitutively open channel Loops A interact withtheir neighbor monomers and they move in the tetramer independently fromeach other.