0. Abbreviations 106

1. Introduction: overview of forces in biology 108

1.1 Subtleties of biological forces and interactions 108

1.2 Specific and non-specific forces and interactions 113

1.3 van der Waals (VDW) forces 114

1.4 Electrostatic and ’double-layer‘ forces (DLVO theory) 122

1.4.1 Electrostatic and double-layer interactions at very small separation 126

1.5 Hydration and hydrophobic forces (structural forces in water) 131

1.6 Steric, bridging and depletion forces (polymer-mediated and tethering forces) 137

1.7 Thermal fluctuation forces: entropic protrusion and undulation forces 142

1.8 Comparison of the magnitudes of the major non-specific forces 146

1.9 Bio-recognition 146

1.10 Equilibrium and non-equilibrium forces and interactions 150

1.10.1 Multiple bonds in parallel 153

1.10.2 Multiple bonds in series 155

2. Experimental techniques for measuring forces between biological molecules and surfaces 156

2.1 Different force-measuring techniques 156

2.2 Measuring forces between surfaces 161

2.3 Measuring force–distance functions, F(D) 161

2.4 Relating the forces between different geometries: the ‘Derjaguin Approximation’ 162

2.5 Adhesion forces and energies 164

2.5.1 An example of the application of adhesion mechanics of biological adhesion 166

2.6 Measuring forces between macroscopic surfaces: the surface forces apparatus (SFA) 167

2.7 The atomic force microscope (AFM) and microfiber cantilever (MC) techniques 173

2.8 Micropipette aspiration (MPA) and the bioforce probe (BFP) 177

2.9 Osmotic stress (OS) and osmotic pressure (OP) techniques 179

2.10 Optical trapping and the optical tweezers (OT) 181

2.11 Other optical microscopy techniques: TIRM and RICM 184

2.12 Shear flow detachment (SFD) measurements 187

2.13 Cell locomotion on elastically deformable substrates 189

3. Measurements of equilibrium (time-independent) interactions 191

3.1 Long-range VDW and electrostatic forces (the two DVLO forces) between biosurfaces 191

3.2 Repulsive short-range steric–hydration forces 197

3.3 Adhesion forces due to VDW forces and electrostatic complementarity 200

3.4 Attractive forces between surfaces due to hydrophobic interactions: membrane adhesion and fusion 209

3.4.1 Hydrophobic interactions at the nano- and sub-molecular levels 211

3.4.2 Hydrophobic interactions and membrane fusion 212

3.5 Attractive depletion forces 213

3.6 Solvation (hydration) forces in water: forces associated with water structure 215

3.7 Forces between ‘soft-supported’ membranes and proteins 218

3.8 Equilibrium energies between biological surfaces 219

4. Non-equilibrium and time-dependent interactions: sequential events that evolve in space and time 221

4.1 Equilibrium and non-equilibrium time-dependent interactions 221

4.2 Adhesion energy hysteresis 223

4.3 Dynamic forces between biomolecules and biomolecular aggregates 226

4.3.1 Strengths of isolated, noncovalent bonds 227

4.3.2 The strengths of isolated bonds depend on the activation energy for unbinding 229

4.4 Simulations of forced chemical transformations 232

4.5 Forced extensions of biological macromolecules 235

4.6 Force-induced versus thermally induced chemical transformations 239

4.7 The rupture of bonds in series and in parallel 242

4.7.1 Bonds in series 242

4.7.2 Bonds in parallel 244

4.8 Dynamic interactions between membrane surfaces 246

4.8.1 Lateral mobility on membrane surfaces 246

4.8.2 Intersurface forces depend on the rate of approach and separation 249

4.9 Concluding remarks 253

5. Acknowledgements 255

6. References 255

While the intermolecular forces between biological molecules are no different from those that arise between any other types of molecules, a ‘biological interaction’ is usually very different from a simple chemical reaction or physical change of a system. This is due in part to the higher complexity of biological macromolecules and systems that typically exhibit a hierarchy of self-assembling structures ranging in size from proteins to membranes and cells, to tissues and organs, and finally to whole organisms. Moreover, interactions do not occur in a linear, stepwise fashion, but involve competing interactions, branching pathways, feedback loops, and regulatory mechanisms.