Membrane Permeability and Driving Forces: Why Molecules Move

Gradients: the reason there is net movement

Molecules are always moving randomly due to thermal energy. What creates net movement (a predictable overall flow in one direction) is a gradient: a difference across space. When a gradient exists, more particles will move from the side with “more driving force” to the side with “less driving force,” even though individual particles still move in all directions.

Two major kinds of gradients matter for membrane transport: differences in concentration and differences in electrical charge. Many biologically important solutes (ions) are affected by both at the same time.

Concentration gradient: “crowding” pushes diffusion

A concentration gradient exists when a substance is more concentrated on one side than the other. Net diffusion tends to go from high concentration to low concentration.

• Example (O₂): If O₂ is higher in blood than in a tissue cell, O₂ will diffuse into the cell.
• Example (CO₂): If CO₂ is higher inside tissues than in blood, CO₂ will diffuse out into blood.

For uncharged molecules, the concentration gradient is usually the main driver of net movement.

Electrical gradient: charge differences pull ions

An electrical gradient exists when there is a difference in voltage (charge separation) across a membrane. Because like charges repel and opposite charges attract, an electrical gradient can pull ions toward the side with opposite charge.

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• Example (Na⁺): If the inside of a cell is relatively negative compared with the outside, the electrical gradient tends to pull positively charged Na⁺ inward.
• Example (Cl⁻): A negative interior tends to push negatively charged Cl⁻ outward (or resist its entry), depending on the concentration gradient.

Electrical gradients matter only for charged solutes (ions) and are irrelevant for neutral molecules like glucose or O₂.

Electrochemical gradient: concentration + electrical together

For ions, the true “push” is the electrochemical gradient, which combines:

• Chemical (concentration) force: from high to low concentration
• Electrical force: toward opposite charge

These forces can reinforce each other or oppose each other.

When forces reinforce

If Na⁺ is higher outside the cell than inside (concentration gradient inward) and the inside is negative (electrical gradient inward), both forces point inward. Net movement inward will be strongly favored if a pathway exists.

When forces oppose

If an ion is higher outside (concentration gradient inward) but the inside is positive (electrical gradient outward for cations), the two forces compete. Net direction depends on which force is stronger. In physiology, this is why changing membrane voltage can change the direction or magnitude of ion flow through channels.

Permeability rules: which molecules cross the lipid bilayer easily?

Even with a strong gradient, a molecule cannot cross quickly unless the membrane is permeable to it. A useful rule of thumb for crossing the lipid bilayer (without transport proteins) is:

Small nonpolar > small uncharged polar > large polar/charged

Small nonpolar: cross easily

• O₂ and CO₂: small and nonpolar, dissolve in the lipid core and diffuse rapidly. This is why respiratory gases move quickly across membranes when a gradient exists.

Small uncharged polar: cross slowly to moderately

• Water (H₂O): polar but small; it can cross the bilayer slowly, but in many cells most water movement occurs through aquaporin channels (when present), which greatly increases permeability.
• Urea: small and uncharged but polar; crosses some membranes slowly and may also use specific urea transporters in certain tissues.

Large polar molecules and charged solutes: effectively blocked without proteins

• Glucose: large and polar; despite being uncharged, it crosses the lipid bilayer extremely poorly. Cells rely on glucose transporters (e.g., GLUT family) to move it across.
• Na⁺ (and other ions): charged and surrounded by a hydration shell in water; the lipid core is a major barrier. Ions generally require ion channels or transporters to cross at physiologically meaningful rates.

Practical implication: gradients tell you the direction of driving force, but permeability (often determined by the presence of channels/transporters) determines whether movement is fast, slow, or negligible.

A reusable prediction framework

Use this step-by-step method whenever you are asked to predict membrane movement. It works for gases, water, nutrients, and ions.

Step 1: Identify the solute

Ask: Is it small and nonpolar (O₂, CO₂)? Small uncharged polar (water, urea)? Large polar (glucose)? Charged (Na⁺)?

• Why it matters: This determines baseline permeability through the lipid bilayer and whether electrical forces apply.

Step 2: Identify the barrier and available pathways

Ask: Are we talking about crossing a lipid bilayer directly, or is there a known protein pathway (channel/transporter) present?

• Rule: If no channel/transporter is available, ions and large polar molecules will have extremely low flux even with a strong gradient.
• Rule: If a channel is open, permeability can jump dramatically, and the gradient becomes the main determinant of direction.

Step 3: Identify the gradient(s)

Determine what differences exist across the membrane.

• Concentration gradient: compare concentrations on each side.
• Electrical gradient (ions only): compare membrane voltage; decide which side is relatively negative/positive.
• Electrochemical gradient (ions): combine the two to see whether they reinforce or oppose.

Step 4: Predict direction and relative rate

Direction comes from the gradient(s); rate comes largely from permeability and pathway availability.

• Fast: small nonpolar gases (O₂, CO₂) with a gradient.
• Variable: water (slow through bilayer, fast with aquaporins).
• Slow: small uncharged polar like urea (often limited, sometimes assisted).
• Very slow/negligible without proteins: glucose and ions like Na⁺.

Worked mini-examples using the framework

Example 1: Why CO₂ leaves tissues quickly

• Solute: CO₂ (small, nonpolar).
• Barrier: lipid bilayers of tissue cells and capillary endothelium; CO₂ can dissolve in membranes.
• Gradient: CO₂ is produced by metabolism, so its concentration (and partial pressure) is higher in tissues than in incoming blood.
• Prediction: net diffusion from tissue → blood, and it is rapid because permeability is high.

Example 2: Why Na⁺ needs proteins even if the driving force is strong

• Solute: Na⁺ (charged).
• Barrier: lipid bilayer is a strong barrier to charged particles.
• Gradient(s): often Na⁺ concentration is higher outside than inside (chemical drive inward) and the inside is relatively negative (electrical drive inward), producing a strong inward electrochemical gradient.
• Prediction: despite a strong inward driving force, Na⁺ flux is minimal unless Na⁺ channels are open or a transporter is present; with an open channel, Na⁺ can move inward rapidly.

Example 3: Glucose across a membrane

• Solute: glucose (large, polar, uncharged).
• Barrier: lipid bilayer blocks it effectively.
• Gradient: may favor entry (higher outside) or exit (higher inside), depending on tissue and timing.
• Prediction: direction follows the concentration gradient only if a glucose transporter is present; rate depends on transporter number and activity, not on bilayer permeability.

Physiology connection: fast gas exchange vs protein-dependent ion movement

In active tissues, metabolism continuously generates CO₂, maintaining a concentration (partial pressure) gradient from tissue to blood. Because CO₂ is small and nonpolar, membranes are highly permeable to it, so it diffuses out quickly.

By contrast, ions such as Na⁺ are strongly excluded by the hydrophobic membrane interior. Even when the electrochemical gradient strongly favors movement, meaningful ion flow requires membrane proteins (channels or transporters) to provide a polar pathway. This is why controlling the opening and closing of ion channels is such a powerful way for cells to regulate electrical signaling and solute balance.