What is a key factor that limits the maximum possible (fastest) association rate constant (kon) for ligand binding?

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BlackTom AI · Accepted Answer

Restating the question: What is a key factor that limits the maximum possible (fastest) association rate constant (kon) for ligand binding?

Option 1: Ligands with higher molecular weight always have a higher kon. This is not correct because kon is governed largely by how fast the ligand can reach the binding site (diffusion) and the intrinsic binding process, not simply by molecular weight. Heavier ligands often diffuse more slowly, which can reduce kon rather than increase it, so weight alone does not guarantee a higher kon.

Option 2: kon can be increased indefinitely by increasing ligand concentration. This is a misconception. kon is an intrinsic rate constant describing the speed of association per unit concentration; increasing concentration affects the rate of observed binding (kobs) but does not raise the intrinsic kon itself. At high concentrations, you may observe more rapid binding events, but the fundamental kon value is constrained by physical diffusion and molecular interaction limits.

Option 3: The presence of an allosteric inhibitor always increases kon. Allosteric inhibitors typically reduce or modulate binding by altering receptor conformation or accessibility, often decreasing the rate of association in some contexts. It is not universally true that allosteric inhibitors increase kon; in many cases they decrease or modulate it downward, making this statement incorrect.

Option 4: The maximum kon is determined by the strength of hydrogen bonding between the ligand and receptor. While hydrogen bonding can influence binding affinity and orienting interactions, the fastest possible association rate is not limited primarily by hydrogen bond strength. Very rapid association can be diffusion-limited, and even strong hydrogen bonds cannot overcome diffusion constraints to produce arbitrarily high kon. Thus this option misidentifies the dominant limiting factor for the fastest kon.

Option 5: The maximum kon is limited by the rate at which molecules diffuse through water to reach the target. This is correct because, in solution, diffusion sets an upper bound on how quickly molecules can encounter each other. If the encounter rate is diffusion-limited, kon cannot exceed the rate at which ligand and receptor find each other, regardless of how favorable the subsequent binding interaction might be. This aligns with physical chemistry principles describing diffusion-controlled reactions.

In summary, among all choices, the diffusion limit (Option 5) is the key factor constraining the fastest possible association rate constant, while the other options either misstate how kon scales with concentration, misattribute the limiting factor, or describe effects that do not universally increase kon.

2254 BIOSC 1544 SEC1000 Quiz #9: Ligand Binding Mechanisms

What is a key factor that limits the maximum possible (fastest) association rate constant (kon) for ligand binding?

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