Polar and charges residues tend to be on the surface inside( surface, inside ) making H-bonding contact with water amino acids( water, amino acids ).
Polar backbone amide groups dragged into the more hydrophobic interior of the protein satisfy their H-bonds by forming secondary primary tertiary( secondary, primary, tertiary ) structural elements with other main chain donors and acceptors.
Not all hydrophobic hydrophylic( hydrophobic, hydrophylic ) residues can be buried and some are found in contact with water. This unfavourable outcome is offset by the many more favourable contacts made in the protein as a whole.
When hydrophobic residues cluster on the surface of a protein they usually from part of a specific binding inhibiting( binding, inhibiting ) site or form a patch of mutually interacting non-polar polar( non-polar, polar ) groups.
Protein folding is a thermodynamic compromise and is energetically very complex favourable slow( complex, favourable, slow ). Suffice it to say that although there are many hundreds of interactions stabilising a folded protein the difference in free energy between the folded and unfolded state is generally not that large large( not that large, large ).

Some water molecules can be trapped inside the tertiary secondary primary quaternary( tertiary, secondary, primary, quaternary ) structure of proteins in internal cavities or in clefts/interfaces etc. These water molecules are all part of the tertiary structure secondary structure primary structure quaternary structure( tertiary structure, secondary structure, primary structure, quaternary structure ) and may be important for the proteins functional activity.

Because most of the forces that stabilise tertiary structure are non-covalen covalent( non-covalen, covalent )t these weak interactions can break and reform readily.
Thus a protein molecule is more flexible than a molecule in which only covalent forces stabilse non-covalent forces stabilise covalent forces disrupt non-covalent forces disrupt( covalent forces stabilse, non-covalent forces stabilise, covalent forces disrupt, non-covalent forces disrupt ) the structure.
Protein structures continually fluctuate around an equilibrium structure as seen in this molecular dynamics simulation of interactions between two helices beta sheets( helices, beta sheets ).
In proteins fluctuations in shape can vary from tiny ones of hundreths of an Angstrom Armstrongs Kelvin Joules Moles Amstrons( Angstrom, Armstrongs, Kelvin, Joules, Moles, Amstrons ) to very large movements of a segment of a structure relative to the rest of the molecule.
This type of flexibility is often key to protein function. Eg. An enzyme might change shape upon binding substrate or a receptor when it binds its agonist antagonist protagonist acceptor site( agonist, antagonist, protagonist, acceptor site ).

A protein tertiary quaternary primary secondary( tertiary, quaternary, primary, secondary ) structure is the most thermodynamically stable structure achievable in aqueous solution. It is primarily driven by the hydrophobic hydrophilic( hydrophobic, hydrophilic ) effect and by a series of many non-covalent covalent( non-covalent, covalent ) forces. There are however some addition stabilising factors which aid in the formation of the most appropriate tertiary structure primary structure quaternary structure secondary structure( tertiary structure, primary structure, quaternary structure, secondary structure ).
Many proteins are additionally stabilised by disulphide phosphodiester hydrogen( disulphide, phosphodiester, hydrogen ) bonds between segments of secondary structure in the native state. These proteins go through many intermediates on the folding pathway and tend to be more stable than tertiary structures than secondary structure than primary structure than quaternary structure( than tertiary structures, than secondary structure, than primary structure, than quaternary structure ) without covalent interactions. Proteins that have disulphide bonds phosphodiester bonds hydrogen bonds( disulphide bonds, phosphodiester bonds, hydrogen bonds ) (formed between appropriately positioned cyteine residues), include immunoglobulins, ribonuclease, insulin and pancreatic trypsin inhibitor (shown here).

The coordination of a metal ion to several protein side chains is a quite common stabilising inhibition binding( stabilising, inhibition, binding ) factor in proteins. 30% 40% 50% 60%( 30%, 40%, 50%, 60% ) of all proteins have metal ions associated with them and the bonding can be very tight or very loose. Water DNA Sulphate Oxygen Cofactors( Water, DNA, Sulphate, Oxygen, Cofactors ) can also be involved in this interaction. The most common stabilising metal ions are calcium iron mercury( calcium, iron, mercury ) and zinc although potassium and sodium are also sometimes found. Stabilising metal ions are distinct from metal ions found in the active site binding site inhibition site( active site, binding site, inhibition site ) of metalloproteins and they have no chemical function other than providing stability.

Quarternary structures are held together by non-covalent covalent( non-covalent, covalent ) forces allowing inhibiting( allowing, inhibiting ) movements between subunits and at the interfaces between subunits

Tight binding between subunits can be achieved if there are a large enough number of weak interactions at the interface binding site( interface, binding site )
This is maximised if the interfaces if the binding sites( if the interfaces, if the binding sites ) fit closely together.
This principle of complementarity is observed in all binding interactions in proteins whether it is at interfaces or at binding sites for ligands inhibitors( ligands, inhibitors ) or substrates.
Importantly, complementarity does not rule out flexibility in the protein molecule as we shall see later flexibility is key to the function structure properties( function, structure, properties ) of many proteins.

The flexibility complementarity( flexibility, complementarity ) of proteins is seen in many different forms of motion. The timescales energy sources( timescales, energy sources ) of these movements dictate the type of events that the motion is associated with. Very fast and small scale motions tend to be associated with catalysis with binding with signalling( with catalysis, with binding, with signalling ), whereas collective mid range spatial and temporal motions are associated with conformational changes upon binding or signalling upon binding or catalysis upon catalysis or signalling( upon binding or signalling, upon binding or catalysis, upon catalysis or signalling ). Slow and large scale motions in proteins are often associated with binding events catalytic events signalling events( binding events, catalytic events, signalling events ). Many of these movements involve the release of bound water molecules amino acid residues( water molecules, amino acid residues ) and the making/breaking of non-covalent covalent( non-covalent, covalent ) interactions as the protein moves or subunits move relative to one another.

Triosephospahte isomerase shows specific localised large movements on binding active( binding, active ) substrate. An eight seven six( eight, seven, six ) residue loop (red) is in the open configuration prior to substrate binding and closed down over the bound substrate to exclude solvent solute( solvent, solute ) (blue) upon binding inhibition( binding, inhibition ). You will note that this is a localised shape bond charge( shape, bond, charge ) change and that the main body of the protein does not really change shape. Such triggered conformational changes can be quite large small( large, small ) in proteins and it is the unique structure of proteins and the inherant flexibility/instability of the molecules that allows this to happen.