Pre-transition effects mediate forces of assembly between transmembrane proteins (1506.04298v4)

Abstract: We present a mechanism for a generic and powerful force of assembly and mobility for transmembrane proteins in lipid bilayers. This force is a pre-transition (or pre-melting) effect for the first-order transition between ordered and disordered phases in the host membrane. Using large scale molecular simulation, we show that a protein with hydrophobic thickness equal to that of the disordered phase embedded in an ordered bilayer stabilizes a microscopic order-disorder interface, and the stiffness of that interface is finite. When two such proteins approach each other, they assemble because assembly reduces the net interfacial free energy. In analogy with the hydrophobic effect, we refer to this phenomenon as the "orderphobic effect". The effect is mediated by proximity to the order-disorder phase transition and the size and hydrophobic mismatch of the protein. The strength and range of forces arising from the orderphobic effect are significantly larger than those that could arise from membrane elasticity for the membranes we examine.

• The paper identifies the "orderphobic effect," mediated by lipid phase transitions, as a novel mechanism driving the assembly of transmembrane proteins in cellular membranes.
• Molecular dynamics simulations show these orderphobic forces are stronger and have a larger range than elasticity predictions, with interfacial stiffness measured at 11.5 pN.
• This newly recognized effect provides insights into membrane organization like lipid rafts and how protein function is modulated, with implications for drug discovery and biomimetic systems.

Mechanisms of Protein Assembly in Lipid Bilayers: The Orderphobic Effect

The paper "Pre-transition effects mediate forces of assembly between transmembrane proteins" by Katira et al. explores a crucial aspect of cellular membrane dynamics — the self-assembly and mobility of transmembrane proteins within lipid bilayers. This paper investigates the physicochemical principles governing the lateral organization of proteins in biological membranes, emphasizing a novel mechanism akin to the hydrophobic effect, named the "orderphobic effect."

Main Findings

The authors use molecular dynamics simulations to elucidate how transmembrane proteins, whose hydrophobic thickness aligns with the disordered phase of lipid bilayers, can induce coalescence through an order-disorder phase transition in the membrane. Such proteins are found to stabilize order-disorder interfaces, termed as "orderphobic," which balance the interfacial free energy, resulting in enhanced protein assembly.

Key numerical results include:

• The strength and range of forces from the orderphobic effect were noted to be larger than those predicted by membrane elasticity alone, particularly within the lipid models examined.
• Interfacial stiffness measurements, using capillary wave theory, estimate a significant value of 11.5 pN, highlighting the association with the phase transition.
• For proteins akin to KALP23, the disordering effect induced by the protein side chains further enhances 'orderphobicity', despite minimal hydrophobic length mismatch.

Theoretical and Practical Implications

This research provides an important insight into the lateral organization within cellular membranes, bridging the gap between theoretical phase transition models and biological membrane dynamics. The recognition of the orderphobic effect opens new pathways to understanding lipid-protein interactions, with potential implications for fields ranging from biochemistry to pharmacology.

From a practical standpoint, the orderphobic effect can elucidate the organization seen in lipid rafts and other microdomain structures within membranes. It suggests mechanisms for the clustering of signaling molecules and the modulation of membrane protein functions. Such understanding may influence the development of therapeutic strategies targeting membrane protein interactions and the design of biomimetic systems.

Discussion and Future Directions

This paper highlights several avenues for future research:

• Investigating the role of orderphobicity in the distribution of various transmembrane proteins, especially in complex biological membranes with diverse lipid compositions and protein arrangements.
• Exploring how the effect could be modulated to control processes like membrane fusion and protein segregation, both of which are vital for cellular signaling and transport processes.
• Assessing the influence of environmental factors, such as temperature and pressure, on the order-disorder transitions in lipid bilayers, and consequently on membrane-protein interactions.

In conclusion, Katira et al. have presented a compelling mechanism for protein assembly in lipid bilayers that aligns with physical principles of phase transitions. The implications of their work shed light on the intricate behaviors within cellular membranes and provide a basis for future explorations that connect molecular scale phenomena with larger biological functions.