Sarcolipin (SLN), an important membrane protein expressed in the sarcoplasmic reticulum (SR), regulates muscle contractions in cardiac and skeletal muscle. The phosphorylation at amino acid Thr5 of the SLN protein modulates the amount of Ca(2+) that passes through the SR. Using molecular dynamics simulation, we evaluated the phosphorylation at Thr5 of pentameric SLN (phospho-SLN) channel's energy barrier and pore characteristics by calculating the potential of mean force (PMF) along the channel pore and determining the diffusion coefficient. The results indicate that pentameric phospho-SLN promotes penetration of monovalent and divalent ions through the channel. The analysis of PMF, pore radius and diffusion coefficient indicates that Leu21 is the hydrophobic gate of the pentameric SLN channel. In the channel, water molecules near the Leu21 pore demonstrated a clear hydrated-dehydrated transition; however, the mutation of Leu21 to an Alanine (L21A) destroyed the hydrated-dehydrated transitions. These water-dynamic behaviors and PMF confirm that Leu21 is the key residue that regulates the ion permeability of the pentameric SLN channel. These results provide the structural-basis insights and molecular-dynamic information that are needed to understand the regulatory mechanisms of ion permeability in the pentameric SLN channel.
Keywords: Ion-channel; MD simulation; PMF; Phosphorylation; Sarcolipin.
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