Combining Simulations & Experiments to Explore Interactions Between

Combining Simulations & Experiments to Explore Interactions Between Membranes & Small Molecules Dr Evelyne Deplazes COMBINING SIMULATIONS & EXPERIMENTS TO EXPLORE INTERACTIONS BETWEEN MEMBRANES & SMALL MOLECULES Many important processes in our bodies rely on the transport of small molecules and ions across cell membranes. However, these processes can be extremely intricate and complex, and are frustratingly difficult to study.Dr Evelyne Deplazes and her team at the University of Queensland and the University of Technology have been investigating these processes by combining the best elements of experimental and computational membrane biophysics. This research could help us better understand the way our bodies work, with exciting implications for biotechnology and drug development. Movement of Ions and Molecules ‘The transport of small molecules across membranes is important to understand Of the many complex processes that both fundamental biological processes take place in our bodies, one of the as well as for many applications in most important is the transport of biotechnology and drug development,’ ions and small molecules into and explains Dr Evelyne Deplazes, researcher out of our cells. Each of our cells is at the University of Queensland. enclosed by a membrane made up of fatty molecules called phospholipids, Unfortunately, due to their complexity, which protects the cell’s interior from these interactions are extremely the external environment, and controls challenging to study in the laboratory. which substances can pass through. Computational chemists have Exploring Sodium and Potassium When an ion or molecule interacts with developed simulations that allow for Transport the surface of a cell, the membrane can more in-depth analysis, but these are allow it to pass through under the right not without their own limitations based Dr Deplazes and her colleagues began conditions. However, the nature of these on processing power and computation their investigations by using ‘tethered interactions is not yet fully understood. time. These simulations also need to membranes’, which are essentially be validated, ideally by comparing their phospholipid molecules anchored to Naturally, scientists have been results to experimental data collected a substrate made of pure gold. These searching for new ways to study these from the system being simulated. Dr model membranes mimic the fluidity processes in order to learn more about Deplazes and her colleagues have been that would be found in a cell membrane, them. Such improved knowledge would tackling these issues by using a unique but in an environment where lipid be invaluable for numerous different combined method. composition and other variables such research fields – from understanding as pH and ion concentrations can how certain diseases develop to be controlled. This allows the team designing effective methods for to isolate different effects in a way delivering drug molecules into cells. that is usually not feasible using cell membranes. WWW.SCIENTIA.GLOBAL By measuring the electrical properties sodium was more likely to interact with The process of viruses taking over the of the membrane in the presence of multiple phospholipid molecules than body’s cells is referred to as viral- different concentrations of sodium potassium. Sodium was also more membrane fusion. Scientists have and potassium ions, the team was able likely to be found at the surface of the studied this process extensively, to to learn more about how these two membrane. Dr Deplazes explains that better understand how exactly viruses important ions interact with the surface. these differences could be leading to can pass through the cell membrane. Sodium and potassium ions play key a change in the way the molecules are Understanding how the virus does this roles in countless biological processes, able to move on the surface, hence a may help scientists to identify ways to including water regulation, muscle change in conductance. prevent it from happening. An improved contraction and the transmission of understanding of this process would nerve signals. This study has not only generated also be invaluable for vaccine research, valuable information on the way as many of today’s vaccines – including At low concentrations, the researchers in which our cells can interact with some of those for COVID-19 – deliver found that sodium decreased the ions, but also made a strong case genetic code to our cells inside a membrane’s electrical conductance, for the effectiveness of combining harmless viral ‘shell’. while potassium increased this property. computational and experimental However, they only observed this effect methods for probing biophysical Scientists have previously explored how with certain types of phospholipid mechanisms. viruses penetrate the cell membrane membranes, and not others, implying using a special molecule called ‘GALA’ that the effect was caused by specific Membrane Pores – a synthetic protein designed to interactions between the phospholipid mimic the way viruses interact with molecules and the ions. Nearly every disease-causing virus we phospholipid membranes. Dr Deplazes know about interacts with our bodies and her team have been investigating To further investigate this phenomenon, in a similar way: by entering our cells how GALA molecules are able to open the team implemented molecular through the outer membrane. Once the pores in the cell membrane, by using dynamics simulations. This virus is inside a cell, it can start hijack a combination of experiments and computational approach is used in the cell’s machinery and start replicating molecular dynamics simulations. chemistry research to simulate the itself, allowing it to spread to other ways in which molecules interact with cells. This is done by all kinds of viruses, It was already understood that, under each other. From these simulations, including HIV, measles, and the virus acidic conditions, GALA molecules the team gathered data showing that that causes COVID-19. would assemble and insert themselves WWW.SCIENTIA.GLOBAL Dr Deplazes and her team’s tethered membrane experiments show that certain phenolic acids, such as caffeic acid, caffeic acid methyl ester and kojic acid, change the permeability of phospholipid membranes to varying degrees. In contrast, other phenolic acids with similar structures, including p-coumaric acid, gallic acid and syringic acid, do not alter membrane permeability. To understand why certain phenolic acids can alter membrane structures, while others cannot, the research team performed experiments with different types of phospholipid, to study specific interactions between phenolic acid molecules and the lipid component of phospholipid molecules. They used the data they collected to validate simulations that provide structural information on these interactions. ‘Our results from into the cell membrane to create an open pore. It was these simulations suggest that membrane disruption is related previously believed that each of these pores was made up of to the phenolic acids inducing local and temporal changes at 8–12 individual GALA molecules. Dr Deplazes and the team the water-phospholipid interface without changing the overall have demonstrated that it is more likely that these pores are shape of the membrane,’ says Dr Deplazes. made up of 6 molecules instead. This is important information, as it tells us more about the size of the pores and what they In another study, her team investigated the interaction could let through. ‘This combined approach, for the first time, of steroids and steroid-like molecules with phospholipid directly provides structural information to estimate the size of membranes. Steroids include molecules that naturally pores formed by a peptide similar to the ones found in viruses,’ occur in our body, such as progesterone and testosterone, explains Dr Deplazes. and drugs used to treat inflammatory conditions including arthritis, eczema and asthma. The team’s tethered membrane Furthermore, the team found the pores showed selective experiments showed that these clinically used steroids directly permeability – allowing some ions to enter more easily than alter the permeability of cell membranes. Their results will be others. Their results could represent an important step in useful for designing more effective steroid-based drugs for a learning more about how GALA, and thus viral fusion peptides, range of inflammatory diseases. operate. A Winning Combination How Can Small Molecules Alter Membranes? Throughout her research, Dr Deplazes has demonstrated how Understanding how small molecules interact with phospholipid a combination of computational and experimental chemistry membranes is important for many different applications, can answer questions that one method alone could not. ‘Our including drug development and biotechnology. lab is one of the few labs where biophysical experiments and molecular dynamics simulations are directly combined,’ she By integrating molecular dynamics simulations and says. experiments with tethered membranes, Dr Deplazes and her team have developed a powerful approach to gain Her team’s simulations and tethered membranes are highly valuable insights into molecule–membrane interactions effective for studying molecular interactions in systems at the molecular level. The lab’s ongoing research includes where conditions can be controlled. To translate their studying the membrane-altering effects of steroids, steroid-like findings into living systems, however,

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