TY - JOUR
T1 - A study of the structural properties and thermal stability of human Bcl-2 by molecular dynamics simulations
AU - Ilizaliturri-Flores, Ian
AU - Correa-Basurto, José
AU - Benítez-Cardoza, Claudia G.
AU - Zamorano-Carrillo, Absalom
N1 - Funding Information:
This work was supported by grants from ICyTDF (PIRIVE09-9 and PICSA 1019-6968), CONACYT (CB-132353 and CB-101229), PIFI-SIP-COFAA-IPN, and scholarships to study PhD to IIF and SNI to JCB, CGBC and AZC from CONACYT.
PY - 2014/11/2
Y1 - 2014/11/2
N2 - The anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein interacts with several proteins that regulate the apoptotic properties of cells. In this research, we conduct several all-atom molecular dynamics (MD) simulations under high-temperature unfolding conditions, from 400 to 800 K, for 25 ns. These simulations were performed using a model of an engineered Bcl-2 human protein (Bcl-2-Δ22Σ3), which lacks 22 C-terminal residues of the transmembrane domain. The aim of this study is to gain insight into the structural behavior of Bcl-2-Δ22Σ3 by mapping the conformational movements involved in Bcl-2 stability and its biological function. To build a Bcl-2-Δ22Σ3 three-dimensional model, the protein core was built by homology modeling and the flexible loop domain (FLD, residues 33-91) by ab initio methods. Further, the entire protein model was refined by MD simulations. Afterwards, the production MD simulations showed that the FLD at 400 and 500 K has several conformations reaching into the protein core, whereas at 600 K some of the alpha-helices were lost. At 800 K, the Bcl-2 core is destabilized suggesting a possible mechanism for protein unfolding, where the alpha helices 1 and 6 were the most stable, and a reduction in the number of hydrogen bonds initially occurs. In conclusion, the structural changes and the internal protein interactions suggest that the core and the FLD are crucial components of Bcl-2 in its function of regulate ng access to the recognition sites of kinases and caspases.
AB - The anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein interacts with several proteins that regulate the apoptotic properties of cells. In this research, we conduct several all-atom molecular dynamics (MD) simulations under high-temperature unfolding conditions, from 400 to 800 K, for 25 ns. These simulations were performed using a model of an engineered Bcl-2 human protein (Bcl-2-Δ22Σ3), which lacks 22 C-terminal residues of the transmembrane domain. The aim of this study is to gain insight into the structural behavior of Bcl-2-Δ22Σ3 by mapping the conformational movements involved in Bcl-2 stability and its biological function. To build a Bcl-2-Δ22Σ3 three-dimensional model, the protein core was built by homology modeling and the flexible loop domain (FLD, residues 33-91) by ab initio methods. Further, the entire protein model was refined by MD simulations. Afterwards, the production MD simulations showed that the FLD at 400 and 500 K has several conformations reaching into the protein core, whereas at 600 K some of the alpha-helices were lost. At 800 K, the Bcl-2 core is destabilized suggesting a possible mechanism for protein unfolding, where the alpha helices 1 and 6 were the most stable, and a reduction in the number of hydrogen bonds initially occurs. In conclusion, the structural changes and the internal protein interactions suggest that the core and the FLD are crucial components of Bcl-2 in its function of regulate ng access to the recognition sites of kinases and caspases.
KW - Bcl-2
KW - apoptosis
KW - loop
KW - molecular dynamics
KW - unfolding
UR - http://www.scopus.com/inward/record.url?scp=84905711198&partnerID=8YFLogxK
U2 - 10.1080/07391102.2013.833858
DO - 10.1080/07391102.2013.833858
M3 - Artículo
C2 - 24028527
SN - 0739-1102
VL - 32
SP - 1707
EP - 1719
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 11
ER -