Markovian Backbone Negentropies: Molecular descriptors for protein research. I. Predicting protein stability in Arc repressor mutants.
As more and more protein structures are determined and applied to drug manufacture, there is increasing interest in studying their stability. In this sense, developing novel computational methods to predict and study protein stability in relation to their amino acid sequences has become a significant goal in applied Proteomics. In the study described here, Markovian Backbone Negentropies (MBN) have been introduced in order to model the effect on protein stability of a complete set of alanine substitutions in the Arc repressor. A total of 53 proteins were studied by means of Linear Discriminant Analysis using MBN as molecular descriptors. MBN are molecular descriptors based on a Markov chain model of electron delocalization throughout the protein backbone. The model correctly classified 43 out of 53 (81.13%) proteins according to their thermal stability. More specifically, the model classified 20/28 (71.4%) proteins with near wild-type stability and 23/25 (92%) proteins with reduced stability. Moreover, the model presented a good Mathew's regression coefficient of 0.643. Validation of the model was carried out by several Jackknife procedures. The method compares favorably with surface-dependent and thermodynamic parameter stability scoring functions. For instance, the D-FIRE potential classification function shows a level of good classification of 76.9%. On the other hand, surface, volume, logP, and molar refractivity show accuracies of 70.7, 62.3, 59.0, and 60.0%, respectively.
Chemical Bioactives Center, Central University of "Las Villas," Cuba.
Ronal
R
Ramos de Armas
Humberto
H
González Díaz
Reinaldo
R
Molina
Eugenio
E
Uriarte
D000409:Alanine / Q000737:chemistry; D019943:Amino Acid Substitution; D019295:Computational Biology / Q000379:methods / Q000706:statistics & numerical data; D016002:Discriminant Analysis; D008390:Markov Chains; D008958:Models, Molecular; D015233:Models, Statistical; D009154:Mutation; D011237:Predictive Value of Tests; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins
D012097:Repressor Proteins; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins; D000409:Alanine