title: Substitutions of Amino Acids with Large Number of Contacts in the Native State Have no Effect on the Rates of Protein Folding.
abstract: Various effects of amino acid substitutions on properties of globular proteins have been described in a large number of research papers. Nevertheless, no definite "rule" has been formulated as of yet that could be used by experimentalists to introduce desirable changes in the properties of proteins. Herein we attempt to establish such a "rule". To this end, a hypothesis is proposed on the effects of substitutions of hydrophobic residues with large number of contacts on free energies of different states of a globular protein. The hypothesis states: Substitutions of hydrophobic residues engaged in a large number of residue-residue contacts would not change the folding rate of a protein but could affect its unfolding rate. This hypothesis was verified by both theoretical and experimental analyses, generating a general rule that can facilitate the work of experimentalists on constructing mutant forms of proteins.
authors.affiliation: Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow, Region, Russia. Electronic address: bmelnik@phys.protres.ru.
authors.forename: Bogdan S
authors.initials: BS
authors.lastname: Melnik
authors.affiliation: Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow, Region, Russia.
authors.forename: Galina S
authors.initials: GS
authors.lastname: Nagibina
authors.affiliation: Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow, Region, Russia.
authors.forename: Anatoly S
authors.initials: AS
authors.lastname: Glukhov
authors.affiliation: Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow, Region, Russia.
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Melnik
authors.affiliation: Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia; Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. Electronic address: vuversky@health.usf.edu.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D024402:Carbonic Anhydrase II / Q000737:chemistry / Q000235:genetics; D002417:Cattle; D057927:Hydrophobic and Hydrophilic Interactions; D016297:Mutagenesis, Site-Directed; D011489:Protein Denaturation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D013816:Thermodynamics
chemical_list: D011506:Proteins; D024402:Carbonic Anhydrase II
keywords: Point amino acid substitutions; Protein folding rate; Protein folding transition state; Protein unfolding rate; carbonic anhydrase II