In most cases, mutations in the core of a protein that replace a smaller nonpola

Question

In most cases, mutations in the core of a protein that replace a smaller nonpolar side chain in the wild-type (e.g., Ala, Val) with a larger nonpolar side chain (e.g., Leu, Ile, Phe, Trp) in the mutant, result in significant destabilization and misfolding of the mutant. What feature of the protein core explains this observation? Why would such a mutation prevent a protein from folding properly?

Interactions of (blank) side chains in the protein sequence lead to the formation of a tightly packed (blank) core. This core is stabilized by a (blank) number of (blank). When a mutation occurs, it destabilizes the protein core and weakens (blank) leading to misfolding.

options to fill in blanks:

hydrogen bonds

polar

large

van der Waals contacts

hydrophobic

disulfide bridges

hydrophilic

small

nonpolar

Explanation / Answer

The protein core is found in those protein that have attained a tertiary structure. A tertiary structure is formed because of the hydrophobic interaction between the side chains of amino acid residues. The core of such a protein which has attained three dimensional structure is hydrophobic in nature. All the information needed to fold the protein into its native tertiary structure is contained within the primary structure of the peptide chain itself. Apart from hydrophobic interactions, electrostatic interactions, hydrogen bonds and van der Waals forces also play a role in stabilisation of protein structure. When the protein core containing smaller non-polar side-chain (Ala, Val) is replaced with larger non-polar side chains (Phe, Ile, Leu) , the resulting protein structure is not the native protein structure. Following are the phenomena that are responsible for destabilisation and misfolding of the protein: Replacement of native amino acid residues disturbs the primary structure of the peptide chain that disturbs the overall tertiary structure of protein. Replacement with larger non-polar side chains results in increased bond lenth between the side chains of amino acid residues. Increase in bond length decreases the bond strength and hence the interactive forces become weak and so the protein is destabilised. When we replace the smaller non-polar side chain with the larger ones, it induces the volume change which further destabilises the mutant protein. Interactions of (small) side chains in the protein sequence lead to the formation of tightly packed (hydrophobic) core. This core is stabilized by (large) number of (van der Waals contact). When a mutation occurs, it destabilises the protein core and weakens (hydrogen bonds) leading to misfolding.

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