Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins

@article{citeulike:1232246, abstract = {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 \&\#8220;from both ends of the hydrophobicity scale\&\#8221; 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.}, author = {Berezovsky, Igor N. and Zeldovich, Konstantin B. and Shakhnovich, Eugene I. }, citeulike-article-id = {1232246}, doi = {10.1371/journal.pcbi.0030052\#toclink6}, journal = {PLoS Computational Biology}, keywords = {design, protein}, month = {March}, number = {3}, pages = {e52+}, posted-at = {2007-04-17 16:21:45}, priority = {3}, title = {Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins}, url = {http://dx.doi.org/10.1371/journal.pcbi.0030052\%23toclink6}, volume = {3}, year = {2007} }

TY - JOUR ID - citeulike:1232246 L3 - citeulike-article-id:1232246 TI - Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins JF - PLoS Computational Biology VL - 3 IS - 3 SP - e52 N2 - 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. KW - design KW - protein AU - Berezovsky, Igor AU - Zeldovich, Konstantin AU - Shakhnovich, Eugene PY - 2007/03/01/ UR - http://dx.doi.org/10.1371/journal.pcbi.0030052%23toclink6 ER -