Investigating Biomembranes and Hydrophobic Interactions

1. Berkowitz Research Group Home Research People Publications Contact The focus of our research is to investigate structural and dynamical properties of biomembranes, structure and dynamics of water and aqueous solutions at interfaces and the nature of long ranged “hydrophobic” interactions. We use computer simulation techniques to understand these biological and physiochemical processes at the molecular level. We are currently working on understanding the action of antimicrobial peptides and issues related to understanding the nature of hydrophilic and hydrophobic interactions.

2. Research Action of antimicrobial peptides Current projects AMP Surfactant-coated surfaces Previous research Antimicrobial peptides (AMPs) represent a large class of small peptides that are synthesized by organisms to protect themselves from invading pathogens. This antimicrobial action is accomplished by inducing membrane pores resulting in cell lysis. In our research we study the antimicrobial action of the melittin peptide. Nature of the problem: Events like pore formation by AMP in membranes take place on a longer timescale than we can simulate using a force field with atomic detail. Therefore efficient sampling techniques are crucial to estimate thermodynamic quantities like the free energy to understand the mechanism of the AMP action.

3. A first step to understanding the mode of action of melittin is to understand the behavior of melittin in water, on the membrane surface and in the transmembrane orientation. A striking variation of the effect of these three different environments is displayed in the nature of the secondary structure of melittin. Melittin in water, perpendicular and parallel to the membrane surface. Qualitative analysis of the structural changes alone is not sufficient to explain the antimicrobial action. Thermodynamic quantities like the free energy are necessary to fully understand the mechanism of AMP action. However the accuracy of the free energy calculations depends on the efficiency of sampling. The potential energy surface for these systems are complex and the system gets trapped in a local minimum close to the starting structure. Methods like replica exchange and umbrella sampling help improve the sampling. We currently apply these techniques to study the free energy for the different steps in the AMP pore formation process.

4. Research Surfactant-coated surfaces Current projects - AMP - Surfactant-coated surfaces Previous research One of the ways to prepare hydrophobic surfaces experimentally is to use positively charged surfactants and a mica substrate. In water, the surfactants coat the mica substrate by self-assembly and their hydrophobic tails face water, thus making the surface (consisting of a monolayer of surfactants) hydrophobic. The interaction between such surfactant-coated surfaces is long-ranged and it should be distinguished from the short-range hydrophobic interaction that has its origin in water structure next to the surfaces. The origin of the long-range hydrophobic interaction is still not clear, but it was suggested that it can be due to the electrostatic interactions between the heterogeneously charged surfaces and/or bridging effects due to cavities. Besides, recently it was found that the nature of the interaction is dependent on the type of surfactant counterions.

5. To understand the origin of these long-ranged hydrophobic interactions and the counterion effect (or specific ion effect) on the atomistic scale, we perform atomistic molecular dynamics (MD) simulations with a model system composed of a sheet of mica, counterions and surfactants. Surfactant-coated mica: micelle (left) and monolayer (right) However, even with the fastest computers, studying large-size real-time experimental systems is not possible by employing all-atom MD simulations, since such simulations are computationally very expensive. Therefore we use coarse-grained methodology to study certain aspects of long-range hydration force.

6. Previous Research 1. Molecular Model of a Cell Plasma Membrane In collaboration with scientists at the Academy of Sciences of the Czech Republic, the Berkowitz Group presented molecular dynamics simulations of a multicomponent, asymmetric bilayer in mixed aqueous solutions of sodium and potassium chloride. Because of the geometry of the system, there are two aqueous solution regions in these simulations: one mimics the intracellular region, and one mimics the extracellular region. Ion-specific effects are evident at the membrane/aqueous solution interface. Namely, at equal concentrations of sodium and potassium, sodium ions are more strongly adsorbed to carbonyl groups of the lipid headgroups. Current projects AMP Surfactant-coated surfaces Previous research Snapshot of a double asymmetric membrane with separated interior and exterior solutions.

7. 2. Hydration Force • Recently, we have studied the interaction between phosphatidylcholine bilayers in water, known as hydration force. To understand its origin and molecular details, we employed a model system containing phosphatidycholine headgroups attached to graphene plates (PC−headgroup plates) immersed in water. The potential of mean force (PMF) between PC−headgroup plates shows that the interaction is repulsive and water-mediated interaction plays a major role. Furthermore, thermodynamic analysis indicates that the attractive interaction between polar headgroups and water molecules is responsible for the repulsion. Two PC-headgroup plates 3. Alzheimer’s Disease Research Certain neurodegenerative disorders represent a class of protein aggregation diseases wherein small, misfolded proteins aggregate and lead to deteriorating cellular function. It is imperative to understand the mechanism by which proteins misfold and aggregate in order to develop appropriate treatments for these disorders.

8. Free energy of binding of Aβ to the DPPC bilayer as a function of Aβ-bilayer center of mass separation and number of contacts. In Alzheimer’s disease, one of the most common of these disorders, the Amyloid β (Aβ) peptide is the probable aggregate species. In vitro, Aβ does not aggregate at low peptide concentrations, but the addition of model cell membranes to a low concentration of Aβ leads to aggregation. Recently we performed simulations that attempt to understand a possible mechanism by which membranes influence Aβ aggregation

9. 4. Hydrophobic Interaction and Water behavior Hydrophobic Interaction is a multifaceted phenomenon and thus characterizing or defining hydrophobic interaction is a challenging problem. Along with the recent interest in water behavior in hydrophobic interaction (dewetting phenomena), we investigated water behavior in the confined space between hydrophobic surfaces as well as water-mediated contribution to the free energy change (or PMF) by using simple graphene-like “carbon” plates. Two carbon plates in water

10. 5. Hydrophobic Interaction between Rough Surfaces From the contact angle measurements, it is now well-established that molecular roughness of surfaces enhances hydrophobicity. Inspired by this idea, we studied the effect of roughness on hydrophobic interaction. For this study we used a model plate with rough surface. Molecular simulations clearly demonstrated that the roughness can also enhance the hydrophobic interaction, as well as hydrophobicity. Water droplet on the model rough surface Dewetting phenomenon between model rough surfaces

11. People Prof. Max Berkowitz Postdoctoral members Jhuma Das, PhD Changsun Eun, PhD Sheeba Irudayam, PhD Santo Kolattukudy Poulose, PhD Current Alumni

12. People Prof. Max L. Berkowitz Research Interests Theoretical and Computational Chemistry and Biophysical Chemistry Professional Background Ph.D., Weizmann Institute of Science (1979) M.Sc., Novosibirsk State University (1972) Fellow of the American Physical Society, (elected 1995) Current Alumni

13. People • Jhuma Das • Presently I am studying the interactions of water with surfactant covered surfaces to understand the nature of long-ranged "hydrophobic" interactions. To this end, we investigate surfactant-coated mica surface immersed in water using all-atom molecular dynamics simulation. To study the hydrophobic interactions in larger systems (several tens of nanometers) and compare our results directly with experimental systems, we are also developing new systems based on coarse-grain modeling approach. As a graduate student, I studied protein, lipid and water dynamics in lipid membrane using computational and theoretical modeling. • Research Interests • Long-ranged hydrophobic interactions in surfactant coated surfaces. • Structure-function relationship of membrane proteins, cholesterol etc. in biomolecular systems. • Water at the interface of lipid bilayers, ionic interfaces and within a confined surfaces etc. • Contact: jdas@email.unc.edu Current Alumni

14. People • Changsun Eun • As a graduate student, I studied hydrophilic and hydrophobic interactions between nanoscale particles . Now I work on long-range hydrophobic interaction. • Research Interests • Origin of long-range hydrophobic interaction. • Specific ion effects. • Water dynamics in a confined space and next to surfaces. • Contact: thinkwhy@email.unc.edu Current Alumni

15. People • Sheeba Irudayam • I work on the antimicrobial peptides, evaluating the free energy for the mechanism of action of the AMPs. • Research Interests • Understanding the structure and mechanism of action of cell membrane components. • Drug design. • DNA sequence processing and analysis. • Contact: isheeba@email.unc.edu Current Alumni

16. People • Santo Kolattukudy Poulose • My research interests are mainly in studying biological phenomena involving molecules such as DNA, proteins and lipids using both analytical and computational tools. The methods used make extensive use of statistical mechanics of polymers, chemical dynamics, field theory and coarse-grained and molecular dynamics (MD) simulations. My current interest is in studying equilibrium dynamics of the interaction of antimicrobial peptides with lipid membranes. • Research Interests • Interaction of antimicrobial peptides with lipid membranes • Lipid self-assembly and phase behavior • Collective dynamics of prion proteins • Resist-developer interaction in electron beam lithography • Single chain dynamics of biomolecules • Contact: kolattuk@email.unc.edu Current Alumni

17. Recent Publications 2010 C. Eun and M. L. Berkowitz, Fluctuations in number of water molecules confined between nanoparticles. J. Phys. Chem. B, 114, 13410-13414 (2010). C. H. Davis and M. L. Berkowitz, A molecular dynamics study of the early stages of amyloid- beta(1-42) oligomerization: The role of lipid membranes, Proteins-Structure Functions and Bioinformatics, 78, 2533-2545 (2010). R. Vacha, P. Jurkiewicz, M. Petrov, M. L. Berkowitz et. al., Mechanism of interaction of monovalent ions with phosphatidylcholine lipid membranes, J. Phys. Chem. B, 114, 9504-9509 (2010). C. Eun and M. L. Berkowitz, Thermodynamic and hydrogen-bonding analyses of the interactions between model lipid bilayers, J. Phys. Chem. B, 114, 3013-3019 (2010). 2009 M. L. Berkowitz, Detailed Molecular Dynamics Simulations of Model Biological Membranes Containing Cholesterol. Bioph. Bioch. Acta, 1788 86-96 (2009). C. H. Davis and M.L. Berkowitz, Interaction between Amyloid-beta (1-42) peptide and Phospholipid Bilayer: A Molecular Dynamics Study Biophys. J 96, 785-796 (2009).

18. Robert Vácha, Max L. Berkowitz, and Pavel Jungwirth, Molecular Model of a Cell Plasma Membrane with an Asymmetric Multicomponent Composition: Water Permeation and Ion Effects, Biophys. J. 96, 4493 - 4501 (2009) Zhancheng Zhang and Max L. Berkowitz, Orientational Dynamics of Water in Phospholipid Bilayers with Different Hydration Levels, J. Phys. Chem. B 113, 7676-7680 (2009) Robert Vácha, Shirley W. I. Siu, Michal Petrov, Rainer A. Böckmann, Justyna Barucha- Kraszewska, Piotr Jurkiewicz, Martin Hof, Max L. Berkowitz and Pavel Jungwirth Effects of alkali cations and halide anions on the DOPC lipid membrane, J. Phys. Chem. A 113, 7235- 7243 (2009) C. Eun and M. L. Berkowitz, Origin of the hydration force: Water-mediated interaction between two hydrophilic plates, J. Phys. Chem. B 113, 13222-13228 (2009). C.H. Davis and M.L. Berkowitz, Structure of the Amyloid-beta (1-42) Monomer Absorbed To Model Phospholipid Bilayers: A Molecular Dynamics Study, J. Phys. Chem. B 113, 14480- 14486 (2009)

19. Contact Prof. Berkowitz’s office Caudill 017 maxb@unc.edu Tel: 919-962-1218 Prof. Berkowitz’s lab Caudill 008 Tel: 919-962-0165 Home Research People Publications Contact