Free Energy Landscapes of Encounter Complexes in Protein-Protein Association

Camacho, Carlos J.; Weng, Zhiping; Vajda, Sándor; DeLisi, Charles

doi:10.1016/s0006-3495(99)77281-4

Cited by 179 publications

(204 citation statements)

References 45 publications

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“…4F). The encounter complex is formed when two reactants diffuse sufficiently close to one another for the subsequent binding reaction to occur (27,28). The distance between the two reactants in the encounter complex is used to calculate the concentration at which the intrinsic on-rate in s −1 occurs, and thus to convert to the bulk rate on-rate in M −1 s −1 .…”

Section: Discussionmentioning

confidence: 99%

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Kim

Hudson

Springer

2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the ultralong vascular protein von Willebrand factor (VWF) cause the common human bleeding disorder, von Willebrand disease (VWD). The A1 domain in VWF binds to glycoprotein Ibα (GPIbα) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding. Gain-of-function mutations in A1 and GPIbα in VWD suggest conformational regulation. We report that force application switches A1 and/or GPIbα to a second state with faster on-rate, providing a mechanism for activating VWF binding to platelets. Switching occurs near 10 pN, a force that also induces a state of the receptor−ligand complex with slower off-rate. Force greatly increases the effects of VWD mutations, explaining pathophysiology. Conversion of single molecule k on (s −1 ) to bulk phase k on (s −1 M −1 ) and the k on and k off values extrapolated to zero force for the low-force pathways show remarkably good agreement with bulk-phase measurements.U nderstanding how force affects receptor and ligand binding and unbinding is a long-standing effort in mechanobiology (1-5). Bond dissociation rates typically increase under mechanical stress; however, bond stability can be enhanced through specialized mechanisms induced by force, including catch bonds and switching to a slip bond with a slower off-rate (flex bonds) (6, 7). Bond formation against an applied force has recently been measured (8). Force-regulated switching to a faster on-rate has not yet been reported for any receptor−ligand bond but would have important biological implications for adhesion in environments with high forces such as the circulation.At sites of vascular injury, hydrodynamic force in the bloodstream acting on von Willebrand factor (VWF) is pivotal in regulating the binding of the VWF A1 domain to GPIbα on platelets and commencing the crosslinking of platelets by VWF to form a platelet plug (9-11). VWF circulates in the form of long, disulfidebonded concatemers, with tens to hundreds of monomers, which mostly adopt a compact, irregularly coiled conformation during normal hemodynamics (12). At sites of hemorrhage, flow changes from shear to elongational. On transition from low to high shear and from shear to elongational flow, irregularly coiled molecules extend to a thread-like shape, and elongational (tensile) force is exerted throughout their lengths (13-16). Molecular elongation exposes the multiple A1 binding sites in VWF concatamers for multivalent binding to GPIbα (9,11,14,(16)(17)(18).In vivo, tensile force transmitted through VWF is applied to the N and C termini of individual domains, and could theoretically change A1 domain conformation before binding to GPIbα. Although this scenario has not yet been observed, single-molecule studies demonstrate two distinct force-dependent dissociation pathways (flex-bond behavior) of the wild-type (WT) A1-GPIbα complex, and thus suggest that two conformational states can be present after formation of the receptor−ligand complex (6).Mutations in VWF cause von Willebrand disease (VWD), the most common human heri...

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Section: Discussionmentioning

confidence: 99%

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Kim

Hudson

Springer

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The modern viewpoint suggests the electrostatic complementarity of interacting protein surfaces, instead of charge complementarity [26]. It was proposed that the electrostatic force could promote formation of encounter complexes [27,28] and defines the lifetime of complexes [4].…”

Section: Protein-protein Contacts: Structure Composition and Forcesmentioning

confidence: 99%

Protein‐protein interactions as a target for drugs in proteomics

et al. 2003

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Protein-protein interactions play a central role in numerous processes in the cell and are one of the main fields of functional proteomics. This review highlights the methods of bioinformatics and functional proteomics of protein-protein interaction investigation. The structures and properties of contact surfaces, forces involved in protein-protein interactions, kinetic and thermodynamic parameters of these reactions were considered. The properties of protein contact surfaces depend on their functions. The contact surfaces of permanent complexes resemble domain contacts or the protein core and it is reasonable to consider such complex formation as a continuation of protein folding. Characteristics of contact surfaces of temporary protein complexes share some similarities with active sites of enzymes. The contact surfaces of the temporary protein complexes have unique structure and properties and they are more conservative in comparison with active site of enzymes. So they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations were undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or, on the contrary, to induce protein dimerization.

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“…Furthermore, regarding that only a small fraction of the enzyme surface is involved in the reaction, the Smulochowski equation should be modified further [6], then for typical enzymes, k association is not expected to exceed the value of 10 4 -10 5 M -1 S -1 [7]. However, the association rate constants frequently exceed this theoretical limit [3]. Many models have been suggested to explain this discrepancy [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Directed Ligand Passage over the Surface of Diffusion-Controlled Enzymes: A Cellular Automata Model

Ghaemi

Rezaei‐Ghaleh

Sarbolouki

2004

Lecture Notes in Computer Science

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Abstract. The rate-limiting step of some enzymatic reactions is a physical step, i.e. diffusion. The efficiency of such reactions can be improved through an increase in the arrival rate of the substrate molecules, e.g. by a directed passage of substrate (ligand) to active site after its random encounter with the enzyme surface. Herein, we introduce a cellular automata model simulating the ligand passage over the protein surface to its destined active site. The system is simulated using the lattice gas automata with probabilistic transition rules. Different distributions of amino acids over the protein surface are examined. For each distribution, the hydration pattern is achieved and the mean number of iteration steps needed for the ligand to arrive at the active site calculated. Comparison of results indicates that the rate at which ligand arrives at the active site is clearly affected by the distribution of amino acids outside the active side. Such a process can facilitate the ligand diffusion towards the active site thereby enhancing the efficiency of the enzyme action.

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Free Energy Landscapes of Encounter Complexes in Protein-Protein Association

Cited by 179 publications

References 45 publications

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Protein‐protein interactions as a target for drugs in proteomics

Directed Ligand Passage over the Surface of Diffusion-Controlled Enzymes: A Cellular Automata Model

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