Intrinsic Disorder and Degeneracy in Molecular Scale Organization of Biological Membrane

Abstract

The scale-rich spatiotemporal organization in biological membrane dictates the "molecular encounter" and in turn the larger scale biological processes such as molecular transport, trafficking and cellular signalling. In this work, we explore the degeneracy in lateral organization in lipid bilayer systems from the perspective of energy landscape theory. Our analysis on molecular trajectories show that bilayers with lipids having in-vivo characteristics have a highly frustrated energy landscape as opposed to a funnel-like energy landscape in in-vitro systems. Lattice evolution simulations, with Hamiltonian trained from atomistic trajectories using lipids topology and non-affine displacement measures to characterize the extent of order-disorder in the bilayer, show that the inherent frustration in in-vivo like systems renders them with the ability to access a wide range of nanoscale patterns with equivalent energy penalty. We posit that this structural degeneracy could provide for a larger repository to functionally important molecular organization in in-vivo settings.1 From the emerging field of lipidomics research, it is now known that there are more that 37,500 unique lipid species in Eukaryotic and Prokaryotic cells. The plasma membrane itself has more than 500 different molecular species of lipids. 1-5 One of the fundamental questions in the field is "Why are there so many lipids" ? 6,7 From being considered simply as a "selectively permeable barrier" made up of lipid bilayer, 8-10 it is now well established that lipids in biological membrane have a wide range of functional roles. 11-15 Lipid environments modulate innumerable biological processes 16-27 and in certain cases, specific lipids are critical for a given biological function. For example, protein p24 in COPI machinery recognizes a single sphingolipid species to induce oligomerization and vesicle transport in the ER. 28 Another example in which lipids play a crucial role is that of the very rare highly phosphatidylinositol lipid which drive activation of K+ channels 29,30 besides several other biological functions by specific interactions. 31,32 In all the examples discussed above, lipid interactions range from being extremely non-selective to highly discriminating 33-35 and such a range of interaction is possibly facilitated by their large diversity and chemical complexity. Though the rationale behind diversity in lipid structures in biological membranes is appreciated from the examples related to the folding, dynamics and functions of membrane proteins 36-40 and other molecular-scale processes such as drug binding, 41 and lipid defects driven selective peptide partitioning, 42,43 the evolutionary advantage of such a huge variety and complexity in lipid species is yet to be fully understood especially in the light of the high metabolic expense of lipid synthesis and the cost of maintaining the required lipid homeostasis in the cellular membranes. With the advent of super-resolution imaging techniques, there is now compelling evidence proving that lipid...

Interpretation of Phase Boundary Fluctuation Spectra in Biological Membranes with Nanoscale Organization

“…We recently showed that χ 2 works as a high-fidelity marker between the liquid order (L o ) and liquid disordered (L d ) regions in the membrane system at molecular length scales. 31,50,51 χ 2 was originally applied on the granular material by Falk and Langer 49 and is given as…”

“…Lipids in the L d phase have higher χ 2 values than lipids in the L o phase. 31,50 Detecting Boundaries Using SVM. Identifying molecules at the phase boundaries and measuring the atomic scale motions to quantify the interfacial properties is a challenge in experimental and computational science.…”

“…The energy at the domain boundary is given by the product of line tension and boundary length. Line tension can be tuned based on the chemical composition of the lipid mixture, which manifests as differential molecular interactions ,− and external factors such as temperature that effect distributions at the interface.…”

Interpretation of Phase Boundary Fluctuation Spectra in Biological Membranes with Nanoscale Organization

“…Besides these commonly used markers, we also use the degree of non-affine displacements (χ 2 ) [49] to distinguish between the different phases in the lipid bilayer systems. We recently showed that χ 2 works as a high-fidelity marker between the liquid order (L o ) and liquid disordered (L d ) regions in the membrane system at molecular length scales [31,50,51]. χ 2 was originally applied on granular material by Falk and Langer ( [49]) and is given as:…”

“…The energy at the domain boundary is given by the product of line tension and boundary length. Line tension can be tuned based on the chemical composition of the lipid mixture, which manifests as differential molecular interactions [16,[29][30][31][32] and external factors such as temperature that effect distributions at the interface.…”