Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins
By Igor N. Berezovsky, Konstantin B. Zeldovich, Eugene I. Shakhnovich. 2006
138 citations recorded by the source corpus.
The aim of this work is to elucidate how physical principles of protein design are reflected in natural sequences that evolved in response to the thermal conditions of the environment. Using an exactly solvable lattice model, we design sequences with selected thermal properties. Compositional analysis of designed model sequences and natural proteomes reveals a specific trend in amino acid compositions in response to the requirement of stability at elevated environmental temperature: the increase of fractions of hydrophobic and charged amino acid residues at the expense of polar ones. We show that this “from both ends of the hydrophobicity scale” trend is due to positive (to stabilize the native state) and negative (to destabilize misfolded states) components of protein design. Negative design strengthens specific repulsive non-native interactions that appear in misfolded structures. A pressure to preserve specific repulsive interactions in non-native conformations may result in correlated mutations between amino acids that are far apart in the native state but may be in contact in misfolded conformations. Such correlated mutations are indeed found in TIM barrel and other proteins.
Subfields: Materials Chemistry, Molecular Biology
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Materials Chemistry
- Gideon Lapidoth
- G. Pszolla
- Sarel Jacob Fleishman
- A. Alon
- Michael D. Tyka
- Dror Baran
- Christoffer H Norn
- David Baker
In Molecular Biology
- Sarel Jacob Fleishman
- Gideon Lapidoth
- Christoffer H Norn
- G. Pszolla
- A. Alon
- Michael D. Tyka
- Dror Baran
- David Baker
Citations in the corpus
- AbDesign: an algorithm for combinatorial backbone design guided by natural conformations and sequences (2015, methodology): “18,70 A key advantage of computational design of proteins belonging to a diverse fold family, such as antibodies, is that we can extract statistics regarding amino acid choices on a per-position basis that encode at least some of these elements, and use these statistics to guide the design process.”