The role of site-directed point mutations in protein misfolding

Abstract

A self-consistent mean-field based model is presented to explore the role of site-directed point mutations in designing folded and/or misfolded sequences with a reduced hydrophobic-polar (HP) patterning of amino acids. This site-directed point mutation procedure is developed and applied to both real and lattice proteins to generate a diverse set of sequences. The respective roles of core and surface residues are analyzed with respect to the optimum hydrophobicity required for the structural stability of the protein. The core sites are found to have a critical number of hydrophobic residues, below which a protein may misfold, while the surface sites show a clear preference for the polar residues with the ability to tolerate some hydrophobic residues. Although core sites play an important role in the structural stability of proteins, some specific surface sites are also found to be equally important. A clash and match calculation procedure is proposed, which may be used to predict the number of residue pairs in a sequence with unfavorable and favorable interactions, respectively, due to site-directed point mutations. The number of clashing and matching residue pairs may indicate whether the mutated sequence would be folded or misfolded. The results are independent of the secondary structure topology of the protein. This model may provide new insights into the effect of point mutations on protein stability and may introduce a new method to predict the outcome of a mutation in terms of its probability to fold or misfold.

Effect of site‐directed point mutations on protein misfolding: A simulation study

“…Although, for a given amino acid residue at i th site, the highest correlated amino acid residue at j th site is mutated, yet the misfolding and unfolding probabilities are observed to be quite low. These low misfolding and unfolding probability values demonstrate the tolerance of proteins toward most mutations and only a few site‐directed point mutations can disrupt the structure of the protein . This structural robustness of proteins may be due to the dispersion and dissipation of structural perturbations due to cumulative point mutations .…”

“…The RSA of the amino acid residues in the designed sequences is used to decide whether a given residue in the native state is present at the core or surface. The residues present at sites with RSA < 37 % are considered as core residues, while those at sites with RSA ≥ 37% are denoted as surface residues . The sequence composition plays a vital role in protein folding by introducing amino acid residue specific interactions .…”

“…Hydrophobic residues in globular proteins are mostly present in the core, while hydrophilic residues reside at the surface of the protein. The stability of the native state of a globular protein not only depends on the number of hydrophobic amino acid residues in the core but also on the number of hydrophobic residues at the surface of the protein . Figure depicts the misfolding, ( P [misfold] surf ) and the unfolding, ( P [unfold] surf ) probability of the mutated sequence vs the percentage fraction of the hydrophobic residues at the surface.…”

“…Although globular proteins are marginally stable under physiological conditions, yet they are mutationally robust and tolerate most mutations . Various studies on protein mutations probe the underlying relationship among protein sequence, structure and function . These works provide valuable insights as to how the structure and function of proteins alter due to amino acid substitutions through mutations.…”

Magnetic Signatures of Hydroxyl‐ and Water‐Terminated Neutral and Tetra‐Anionic Mn12‐Acetate

“…We suggest that the large changes in magnetic signals associated with the [Mn 12 O 12 (COOR) 16 (HOH) 4 ] to [Mn 12 O 12 (COOR) 16 (OH − ) 4 + 2H 2 ] decomposition could provide a nondestructive spectroscopic method for learning about water decomposition mechanisms in a class of realizable model catalytic systems that have been synthesized recently.Computational methodologies are capable of predicting magnetic spectroscopies using wavefunction-based methods [3] and density-functional methods [4][5][6][7][8] as a function of charge, geometrical structure, and chemical structure. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] When such calculations are compared with measurements on systems undergoing chemical or structural change, they offer the possibility for learning about mechanistic details associated with such changes. Past experiments and calculations provide many examples of how magnetic structure is impacted by charge, chemical, and solvent rearrangements.…”