Point mutations and sequence variability in proteins: redistributions of preexisting populations.
Here we study the effect of point mutations in proteins on the redistributions of the conformational substates. We show that regardless of the location of a mutation in the protein structure and of its type, the observed movements of the backbone recur largely at the same positions in the structures. Despite the different interactions that are disrupted and formed by the residue substitution, not only are the conformations very similar, but the regions that move are also the same, regardless of their sequential or spatial distance from the mutation. This observation leads us to conclude that, apart from some extreme cases, the details of the interactions are not critically important in determining the protein conformation or in specifying which parts of the protein would be more prone to take on different local conformations in response to changes in the sequence. This finding further illustrates why proteins manifest a robustness toward many mutational events. This nonuniform distribution of the conformer population is consistently observed in a variety of protein structural types. Topology is critically important in determining folding pathways, kinetics, building block cutting, and anatomy trees. Here we show that topology is also very important in determining which regions of the protein structure will respond to sequence changes, regardless of the sequential or spatial location of the mutation.
Intramural Research Support Program-Science Applications International Corporation, Laboratory of Experimental and Computational Biology, National Cancer Institute, Building 469, Room 151, Frederick, MD 21702, USA.
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Sinha
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Nussinov
D000263:Adenylate Kinase / Q000737:chemistry / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D001426:Bacterial Proteins; D017122:Bacteriophage T4 / Q000201:enzymology; D002147:Calmodulin / Q000737:chemistry / Q000235:genetics; D014644:Genetic Variation; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007781:Lactoferrin / Q000737:chemistry / Q000235:genetics; D009113:Muramidase / Q000737:chemistry / Q000235:genetics; D009211:Myoglobin / Q000737:chemistry / Q000235:genetics; D017354:Point Mutation; D011228:Prealbumin / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D012259:Ribonuclease, Pancreatic / Q000737:chemistry / Q000235:genetics; D012260:Ribonucleases / Q000737:chemistry / Q000235:genetics; D020539:Sequence Analysis, Protein; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics
D001426:Bacterial Proteins; D002147:Calmodulin; D009211:Myoglobin; D011228:Prealbumin; D011506:Proteins; D000515:alpha 1-Antitrypsin; D000263:Adenylate Kinase; D012260:Ribonucleases; C019760:Bacillus amyloliquefaciens ribonuclease; D012259:Ribonuclease, Pancreatic; D009113:Muramidase; D007781:Lactoferrin; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease