All-Atom Molecular Dynamics Simulations of the K+ Channel Chimera Kv1.2/Kv2.1

Abstract

Voltage-gated K+ channels (Kv) are composed of four subunits, each of which contains six trans-membrane domains (TMs), S1 through S6. The S1-S4 segments comprise the voltage-sensing domain (VS), which senses membrane potential and controls the gating of the pore domain (PD). Although still controversial, the voltage-sensing domain undergoes conformational changes within the membrane electric field, upon membrane depolarization, that is mechanically transferred via the S4-S5 linker to the intracellular gate of the channel. MD simulations of portions of PD and VS regions highlighted the importance of their flexibility for proper channel function. Nevertheless, a comprehensive description of the dynamics of both domains at atomic level has not been provided yet. Here we report the analysis of all-atom multiple molecular dynamics simulations (∼200 ns) of the entire Kv1.2/2.1 chimera, consisting of the α and β chain embedded in a 549 monomer POPC bilayer, and immersed in a box of 135K explicit SPC water molecules at 300 K. We used principal components analysis (PCA) of the Cα atomic fluctuations covariance matrix to analyze the essential subspace that characterizes the channel internal dynamics. Briefly, we observed an up to 4.5 A conformational drift of VS from its starting position. The average RMSF of the S3b-S4 domain was between 1.6 and 3.0 A. Relative to the pore region, i) the second principal component shows that all four VS domains fluctuate in a concerted manner and affect the flexibility of the intracellular gates; ii) the first principal component reveals that T1 domain moves approximately 3.5 A downwards, influencing the local structure and dynamics of the neighboring intracellular gate. Protein-lipids interactions are crucial for channel structure/function. Thus, the contributions of H-bonds and salt-bridges between channel atoms and lipid head-groups on global channel dynamics will be illustrated.