= Solution
A stable native conformation is favoured when its <Gibbs free energy>, including the <protein> and its surrounding <solvent>, is lower than that of competing conformational ensembles under the specified conditions:
$$
\boxed{\Delta G_{\rm fold}=\Delta H_{\rm fold}-T\Delta S_{\rm total}<0.}
$$
Folding greatly reduces the chain's <conformational entropy>, an unfavourable contribution. It can nevertheless gain favourable hydrogen-bonding and packing interactions, van der Waals contacts, screened <electrostatic interactions> and <solvent> <free energy>. In aqueous globular <proteins>, burying nonpolar surface reduces the cost of exposing it to <water>; the <hydrophobic effect> is not an extra covalent attraction between all hydrophobic residues. <Hydrogen bonds> and ionic contacts must be judged relative to the interactions those groups made with <solvent> before folding, so merely counting bonds in the folded structure does not determine <stability>.
The <protein primary structure> determines which contacts and <protein secondary structures> can cooperate. A <free-energy landscape> biased towards compatible contacts permits many routes towards the native ensemble, rather than an exhaustive random search through every conformation. <Folding funnels> describe this bias, while barriers explain metastability and folding rates. Reversible denaturation/refolding experiments show that some <proteins> can recover native structure and activity when suitable conditions are restored, supporting a sequence-encoded thermodynamic tendency without asserting that every <protein folds> unaided.
“Stable” means an <equilibrium> preference and a useful lifetime, not one perfectly rigid shape. Native <proteins> fluctuate and can have several functional conformations; the unfolded ensemble remains populated with relative weight depending on its full <free energy>. Changes of <temperature>, <pH>, <salt>, <solvent>, <ligands> or <pressure> alter the balance, and <molecular chaperones> can prevent <protein aggregation> or assist kinetic access without supplying a different primary sequence. Membrane <proteins> require their appropriate environment, and <intrinsically disordered proteins> need not possess one stable folded state in isolation.
Thus a released stretched chain can gain configurational <entropy> on first recoiling yet later favour a more ordered native structure because the \i[total] <free energy> balance, including <solvent>, is different. <Equilibrium> <stability>, barriers to unfolding and resistance to irreversible <protein aggregation> are distinct properties. The existence of a native minimum alone does not guarantee rapid, reversible folding under every experimental condition.
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