Group of Jeremy J. Ramsden

Physics of Biological Systems

Molecular recognition and assembly

Introduction: the central role of interfaces in biomolecular recognition

Processes occurring at the solid/liquid interface are central to the functioning of cells and organisms. Our aim is to resolve dynamic and structural details of the interaction of molecules in solution with surfaces such as the bilayer lipid membrane, under well-characterized conditions which closely mimic the in vivo environment. A particularly powerful technique in this regard is optical waveguide lightmode spectroscopy (OWLS). It uses light to probe interfacial processes in a totally non-invasive, non-perturbative way, unlike most other techniques, and the molecules under investigation do not require modification with radioactive, fluorescent etc. labels. Membranes incorporating proteins can be built up on the surface of an optical waveguide and their interactions with soluble proteins studied directly in real time.

General literature

Ramsden, J.J. Review of new experimental methods for investigating random sequential adsorption. J. statist. Phys. 73 (1993) 853-877.
Ramsden, J.J. Experimental methods for investigating protein adsorption kinetics at surfaces. Q. Rev. Biophys. 27 (1994) 41-105.
Ramsden, J.J. Puzzles and paradoxes in protein adsorption. Chem. Soc. Rev. 24 (1995) 73-78.
Ramsden, J.J. Dynamics of protein adsorption at the solid/liquid interface. Recent Res. Devel. Phys. Chem. 1 (1997) 133-142.
Ramsden, J.J. Towards zero-perturbation methods for investigating biomolecular interactions. Colloids Surfaces A 141 (1998) 287-294.
Ramsden, J.J. Biospecific interaction analysis using integrated optics techniques. In: Quantitative Analysis of Biospecific Interactions, P. Lundahl, A. Lundqvist and E. Greijer (eds). Amsterdam: Harwood, (1998).
Ramsden, J.J. Kinetics of protein adsorption. In: M. Malmsten, ed., Biopolymers at Interfaces. New York: Dekker (1998).
Ramsden, J.J. OWLS: a versatile technique for sensing with bioarrays. Chimia 53 (1999) 67-71.

This paper gives a succint overview of the technique of optical waveguide lightmode spectroscopy (OWLS), which has been developed by the author at the Biozentrum (Basel University) as a precision tool for investigating the biophysical chemistry of solid/liquid interfaces. After reviewing the fundamentals of the technique, some applications are discussed: membrane structure (including some previously unpublished work on the interaction of mellitin with phospholipid bilayers), the interaction of cytochrome P450 with lipid bilayer membranes, and the association of restriction enzymes with DNA.
Regulation of metabolism

A major area of activity focuses onto understanding in molecular and submolecular detail the mechanisms responsible for a large variety of regulatory functions involving interaction between proteins and phospholipid bilayer membranes. This boils down to understanding how the association of macromolecule A with B changes the affinity of A for macromolecule C. B may be another macromolecule, a small ion or osmolyte, or a surface. For investigating the role of surfaces, the Langmuir-Blodgett technique is used to coat smooth planar optical waveguides with bilayer membranes constituted from selected pure lipids and mixtures; a method has also been perfected for reconstituting natural cell membranes onto waveguides. Current topics include the role of Ca2+, other cofactors, protein phosphorylation and lipid composition in controlling protein adsorption and desorption; and the functional role of two dimensional clustering and crystallization. Large scale numerical simulations are used to help analyze the experimental results in detail.


Ramsden, J.J. Calcium-dependence of laminin binding to phospholipid membranes. Biopolymers 33 (1993) 475-477.
Ramsden, J.J., Bachmanova, G.I. and Archakov, A.I. Kinetic evidence for protein clustering at a surface. Phys. Rev. E. 50 (1994) 5072-5076.
Ramsden, J.J. and Wright, C.S. The interaction between wheat germ agglutinin and membrane incorporated glycophorin A. An optical binding study. Glycoconjugate J. 12 (1995) 113-121.
Vergères, G. and Ramsden, J.J. Binding of MARCKS-related protein (MRP) to vesicular phospholipid membranes. Biochem. J. 330 (1998) 5-11.
Michielin, O., Vergères, G. and Ramsden, J.J. Evidence for myristoylation-induced compaction of MARCKS-related protein. J. Amer. Chem. Soc. 121 (1999) 6523-6526.

This paper addresses the interaction of MARCKS-related protein (MRP) with lipid bilayers. By comparing the association and dissociation kinetics of intact and unmyristoylated MRP to bilayers it is shown that the myristoyl group not only contributes to the affinity for the membrane, but also induces a conformational compactification (presumably to shield the myristoyl moiety from unfavourable interactions with water) which allows the packing density on the membrane surface to be doubled.
Michielin, O., Ramsden, J.J. and Vergères, G. Unmyristoylated MARCKS-related protein (MRP) binds to supported planar phosphatidylcholine membranes. Biophys. Biochim. Acta 1375 (1998) 110-116.
Ramsden, J.J. and Vergères, G. Nonelectrostatic contributions to the binding of MARCKS-related protein to lipid bilayers. Arch. Biochem. Biophys. 371 (1999) 241-245.
J.J. Ramsden, On protein-lipid membrane interactions. Colloids Surfaces B 14 (1999) 77-81.

The interfacial interaction energy is calculated for MARCKS-related protein (MRP) and phospholipid bilayer membranes. The Lewis acid-base force dominates under physiological conditions. The effector domain is a net electron acceptor, and this, rather than its net positive electrostatic charge, accounts for its attraction to lipid membranes, which are strong net electron donors.
Vergères, G. and Ramsden, J.J. Regulation of the binding of MARCKS-related protein to lipid bilayer membranes by calmodulin. Arch. Biochem. Biophys. 378 (2000) 45-50.
Protein adsorption and desorption

A vast number of technological and biomedical processes revolve around adsorption (e.g. chromatography, filtration, dialysis, storage of pharmaceuticals, biocompatibility of surgical implants). We are devoting significant effort to the elucidation of the energy landscape of adsorbing proteins and other biopolymers, which is the key to controlling these processes.

OWLS represents a significant improvement over existing techniques, e.g. tenfold greater sensitivity compared with surface plasmon resonance (SPR) and ellipsometry. OWLS is also much more versatile than SPR; in particular it can be readily used in conjunction with all major biological environments, such as phospholipid bilayers, basement membranes, DNA and polysaccharides.


Ramsden, J.J. and Schneider, P. Membrane insertion and antibody recognition of a glycosyl-phosphatidylinositol-anchored protein: an optical study. Biochemistry 32 (1993) 523-529.
Ramsden, J.J. Concentration scaling of protein deposition kinetics. Phys. Rev. Lett. 71 (1993) 295-298.
Kurrat, R., Ramsden, J.J. and Prenosil, J.E. Kinetic model for serum albumin adsorption: experimental verification. J. chem. Soc. Faraday Trans. 90 (1994) 587--590.
Ramsden, J.J. and Prenosil, J.E. The effect of ionic strength on protein adsorption kinetics. J. phys. Chem. 98 (1994) 5376-5381.
Ramsden, J.J. Report on the Second International Workshop on Random Sequential Adsorption. Theory and Experiment. J. statist. Phys. 79 (1995) 491-496.
Ramsden, J.J., Roush, D.J., Gill, D.S., Kurrat, R.G. and Willson R.C. Protein adsorption kinetics drastically altered by repositioning a single charge. J. Amer. chem. Soc. 117 (1995) 8511-8516.
Kurrat, R., Prenosil, J.E. and Ramsden, J.J. Kinetics of human and bovine serum albumin adsorption at silica-titania surfaces. J. Colloid Interface Sci. 185 (1997) 1-8.
Luthi, P.O., Ramsden, J.J. and Chopard, B. The role of diffusion in irreversible deposition. Phys. Rev. E 55 (1997) 3111-3115.
Ball, V. and Ramsden, J.J. Absence of surface exclusion in the first stage of lysozyme adsorption is driven through electrostatic self-assembly. J. phys. Chem. B 101 (1997) 5465-5469.
Csúcs, G. and Ramsden, J.J. Generalized ballistic deposition of small buoyant particles. J. chem. Phys. 109 (1998) 779-781.
Guemouri, L. Ogier, J. and J.J. Ramsden, J.J. Optical properties of protein monolayers during assembly. J. Ccem. Phys. 109 (1998) 3265-3268.
P.R. Van Tassel, J.J. Ramsden, L. Guemouri, J. Talbot, G. Tarjus and P. Viot. A particle-level model of irreversible protein adsorption with a postadsorption transition. J. Colloid Interface Sci. 207 (1998) 317-323.
Kurrat, R., Wälivaara, B., Marti, A., Textor, M., Tengvall, P., Ramsden, J.J. and Spencer, N.D. Plasma protein adsorption on titanium. Colloids Surfaces B 11 (1998) 187-201.
Ball, V., Lustig, A. and Ramsden, J.J. Lag phases in the adsorption of lysozyme to silica-titania surfaces in the presence of sodium thiocyanate. Part I. Phenomenology. PCCP 1 (1999) 3667-3671.

This report describes the very unusual phenomenon of sigmoidal evolution of protein adsorption at the solid/liquid interface in the presence of sodium thiocyanate. A preliminary interpretation in terms of the nucleation of lysozyme clusters is given.
Bilayer lipid membrane structure

Changes in anisotropy, thickness and packing density in supported planar phospholipid bilayers can be monitored with high precision and excellent time resolution using OWLS. We have been using it to study the interaction of small organic molecules (drugs) and oligopeptides (hormones). Apart from the high sensitivity, a particular advantage is that with this technique, the reversibility of the interactions can be directly investigated. This is rather difficult to do, and is usually not done, with spectroscopic or microcalorimetric investigations of these interactions with the membranes in vesicular form, but unless reversibility is established, the validity of results from the experiments with vesicles remains questionable.


Ramsden, J.J. Partial molar volume of solutes in bilayer lipid membranes. J. phys. Chem. 97 (1993) 4479-4483.
Ramsden, J.J. Partition coefficients of drugs in bilayer lipid membranes. Experientia 49 (1993) 688-692.
Meier, W. and Ramsden, J.J. Surface pressure determines the interaction between poly(oxyethylene) and a surfactant bilayer. J. phys. Chem. 100 (1996) 1435-1438.
Csúcs, G. and Ramsden, J.J. Interaction of phospholipid vesicles with smooth metal oxide surfaces. Biophys. Biochim. Acta 1369 (1998) 61-70.
Csúcs, G. and Ramsden, J.J. Solubilization of planar bilayers with detergent. Biophys. Biochim. Acta 1369 (1998) 304-308.
Ramsden, J.J. Molecular orientation in lipid bilayers. Phil. Mag. B 79 (1999) 381-386.

The article describes measurements of the birefringence of phospholipid bilayers of different alkyl chain lengths. All showed positive birefringence. This is inconsistent with the commonly depicted laminar structure of such membranes, and shows that the predominant orientation of the lipid molecules is perpendicular to the plane of the membrane. Implications for the permeability of the membrane to small hydrophilic or amphiphilic molecules are discussed.
Attachment, growth and spreading of living cells

OWLS has been developed for measuring the rate and hence the energetics of attachment of cells to surfaces in situ. Furthermore, the technique enables the kinetics of morphological change of attached cells to be monitored continuously in situ. This is currently being exploited in collaboration with the Laboratory for Surface Sience and Technology of the ETH, Zurich, to investigate the response of cells to environmental stress, and to develop a new kind of toxicological sensor.


Ramsden, J.J., Li, S.-Y., Heinzle, E. and Prenosil, J.E. Kinetics of adhesion and spreading of animal cells. Biotechnology and Bioengineering. 43 (1994) 939-945.
Li, S.-Y., Ramsden, J.J., Prenosil, J.E. and Heinzle, E. Measurement of adhesion and spreading kinetics of baby hamster kidney and hybridoma cells using an integrated optical method. Biotechnology Prog. 10 (1994) 520-524.
Ramsden, J.J., Li, S.-Y., Heinzle, E. and Prenosil, J.E. An optical method for the measurement of number and shape of attached cells in real time. Cytometry 19 (1995) 97-102.
Chemical and biochemical sensors

A grating coupler incorporated into an optical waveguide is an efficient transducer for converting a (bio)chemical signal into an optical or electrical one. The application of these devices as miniature sensors is being explored. Their excellent compatibility with biological materials makes them promising candidates for in vivo probes of metabolic processes. In addition, fundamental work on the parameters governing the ultimate attainable sensitivity of this type of sensor is being undertaken.


Ramsden, J.J. Sensitivity enhancement of integrated-optics sensors using Langmuir-Blodgett lipid films. Sensors Actuators B 15-16 (1993) 439-442.
Saini, S., Kurrat, R., Prenosil, J.E. and Ramsden, J.J. Temperature dependence of pyrolyzed sol-gel planar waveguide parameters. J. Phys D: Appl. Phys. 27 (1994) 1134-1138.
Ramsden, J.J. Porosity of pyrolyzed sol--gel waveguides. J. mater. Chem. 4 (1994) 1263-1265.
Ramsden, J.J., Bachmanova, G.I. and Archakov, A.I. Immobilization of proteins to lipid bilayers. Biosensors and Bioelectronics 11 (1996) 523-528.
Ramsden, J.J. A dosimeter for oligopeptide hormones. Sensors Actuators B 30 (1996) 107-110.
Ramsden, J.J. and Karrasch, S. Activated Langmuir-Blodgett films for immobilizing proteins on planar surfaces. Sensors and Materials 8 (1996) 469-476.
Goutev, N., Nickolov, Zh.S. and Ramsden, J.J. Waveguide Raman spectroscopy of silica-titania thin films with grating coupling. J. Raman Spectroscopy 27 (1996) 897-900.
Ramsden, J.J., Németh-Sallay, M., Vörös, J. and Szendrö, I. Integrált optikai hullámvezetö szenzor felületi adszorbció viszgálatára. Fizikai Szemle (1997) 281-285.
Ramsden, J.J. Optical Biosensors. J. molec. Recognition 10 (1997) 109-120.
Kurrat, R., Textor, M., Ramsden, J.J., Boeni, P. and Spencer, N.D. Instrumental improvements in optical waveguide lightmode spectroscopy for the study of biomolecule adsorption. Rev. sci. Instrum. 68 (1997) 2172-2176.
Brynda, E., Houska, M., Skvor, J. and Ramsden, J.J. Immobilization of multilayer bioreceptor assemblies on solid substrates. Biosensors Bioelectronics 13 (1998) 165-172.
Ramsden, J.J. Biomimetic protein immobilization using lipid bilayers. Biosensors Bioelectronics 13 (1998) 593-598.
Ramsden, J.J. A sum parameter sensor for water quality. Water Research 33 (1999) 1147-1150.

This report describes the application of OWLS to the measurement of impurities in water. The water to be tested is brought into contact with a coated optical waveguide. Depending on the coating, different components in the water (humus, viruses, organic pollutants, metal ions, etc.) interact with the waveguide and cause a measurable response.

Spontaneous ordered assembly (sometimes called self-assembly) of complex molecules at the solid/liquid interface is the basis of a highly promising novel concept in materials and device engineering. The ultimate goal is the development of low-cost, robust routes to fabricating complex systems. Even the protagonists of this approach admit that present knowledge of the processes involved is extremely rudimentary, however. In collaboration with E.C. Constable (Institute of Inorganic Chemistry, Basel University), we are investigating structures spontaneously formed when large organometallic complexes are brought into contact with a solid/liquid interface. Presently, we are exploring which control parameters are important for determining the appearance of particular structures.


Ramsden, J.J., Lvov, Yu.A. and Decher, G. Optical and X-ray structural monitoring of molecular films assembled via alternate polyion adsorption. Thin solid Films 254 (1995) 246-251.
Constable, E.C., Harverson, P. and Ramsden, J.J. Adsorption of ruthenadendrimers to silica-titania surfaces studied by optical waveguide lightmode spectroscopy (OWLS). J. Chem. Soc. Chem. Comm. (1997) 1683-1684.
Máté, M. and Ramsden, J.J. Colloidal particles efficiently scavenge fatty acid Langmuir-Blodgett films. J. Dispersion Sci. Tech. (in press).
Ramsden, J.J. and Máté, M. Kinetics of monolayer particle deposition. J. chem. Soc. Faraday Trans. 94 (1998) 783-788.
Máté, M. and Ramsden, J.J. Addition of particles of alternating charge. J. chem. Soc. Faraday Trans. 94 (1998) 287-294.
Máté, M., Fendler, J.H., Ramsden, J.J., Szalma, J. and Hórvölgyi, Z. Eliminating surface pressure gradient effects in contact angle determination of nano- and microparticles using a film balance. Langmuir 14 (1998) 6501-6504.

Development, evolution and related topics


Luthi, P.O., Preiss, A., Chopard, B. and Ramsden, J.J. A cellular automaton model for neurogenesis in Drosophila. Physica D 118 (1998) 151--160.
Dér, A and Ramsden, J.J. Evidence for loosening of a protein mechanism. Naturwissenschaften 85 (1998) 353-355.
J.J. Ramsden and J. Vohradský. Zipf-like behavior in procaryotic protein expression. Phys. Rev. E 58 (1998) 7777-7780.

Foundations and history of biophysical chemistry


J.J. Ramsden. Paracelsus-concept and realization. Interaction 3 (in press).
J.J. Ramsden. Biophysical Chemistry. In: Encyclopaedia of Chemical Physics and Physical Chemistry, J.H. Moore and N.D.Spencer, eds. Philadelphia: IOP. (in press).

Recent publications in other areas of biophysical chemistry

Vergères, G., Ramsden, J.J. and Waskell, L. The carboxyl terminus of the membrane-binding domain of cytochrome b5 spans the bilayer of the endoplasmic reticulum. J. biol. Chem. 270 (1995) 3414-3422.
Ramsden, J.J. and Dreier, J. Kinetics of the interaction between DNA and the type IC restriction enzyme StyR124/3I. Biochemistry 35 (1996) 3746-3753.
M.G. Cacace, E.M. Landau and J.J. Ramsden. The Hofmeister series: salt and solvent effects on interfacial phenomena. Q. Rev. Biophys. 30 (1997) 241-278.
Ball, V. and Ramsden, J.J. Influence of D(-) and L(+) tartaric acid on lysozyme adsorption onto a silica-titania surface. Naturwissenschaften 85 (1998) 87-89.
Ball, V. and Ramsden, J.J. Buffer dependence of refractive index increments of protein solutions. Biopolymers 46 (1998) 489-492.
Cs. Nemes, N. Rozlosnik and J.J. Ramsden, Direct measurement of the viscoelasticity of adsorbed protein layers using atomic force microscopy. Phys. Rev. E 60 (1999) 1166-1169.

Scanning force microscopy is used to determine viscoelastic parameters of massed adsorpta of lysozyme. The aqueous medium bathing the protein layer is varied according to the Hofmeister series, with concomitant changes in the surface properties and stability of the protein molecules.
Last updated 1 December 2000