The human mitochondrial outer membrane protein voltage-dependent anion channel isoform 2 (hVDAC2) is a β-barrel metabolite flux channel that is indispensable for cell survival. It is well established that physical forces imposed on a transmembrane protein by its surrounding lipid environment decide protein structure and stability. Yet, how the mitochondrial membrane and protein-lipid interplay together regulate hVDAC2 stability is unknown. Here, we combine experimental biophysical investigations of protein stability with all-atom molecular dynamics simulations to study the effect of the most abundant mitochondrial phosphocholine (PC) lipids on hVDAC2. We demonstrate experimentally that increasing the PC lipid acyl chain length from diC14:0 to diC18:0-PC has a nonlinear effect on the β-barrel. We show that protein stability is highest in diC16:0-PC, which exhibits a negative mismatch with the hVDAC2 barrel. Our simulations also reveal that structural rigidity of hVDAC2 is highest under optimal negative mismatch provided by diC16:0-PC bilayers. Further, we validate our observations by altering the physical properties of PC membranes indirectly using cholesterol. We propose that VDAC plasticity and stability in the mitochondrial outer membrane are modulated by physical properties of the bilayer.
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