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1.
Methods Mol Biol ; 2376: 387-398, 2022.
Article in English | MEDLINE | ID: mdl-34845622

ABSTRACT

We present a detailed heuristic method to quantify the degree of local energetic frustration manifested by protein molecules. Current applications are realized in computational experiments where a protein structure is visualized highlighting the energetic conflicts or the concordance of the local interactions in that structure. Minimally frustrated linkages highlight the stable folding core of the molecule. Sites of high local frustration, in contrast, often indicate functionally relevant regions such as binding, active, or allosteric sites.


Subject(s)
Protein Conformation , Models, Molecular , Protein Folding , Proteins , Thermodynamics
2.
Proc Natl Acad Sci U S A ; 116(10): 4037-4043, 2019 03 05.
Article in English | MEDLINE | ID: mdl-30765513

ABSTRACT

Conflicting biological goals often meet in the specification of protein sequences for structure and function. Overall, strong energetic conflicts are minimized in folded native states according to the principle of minimal frustration, so that a sequence can spontaneously fold, but local violations of this principle open up the possibility to encode the complex energy landscapes that are required for active biological functions. We survey the local energetic frustration patterns of all protein enzymes with known structures and experimentally annotated catalytic residues. In agreement with previous hypotheses, the catalytic sites themselves are often highly frustrated regardless of the protein oligomeric state, overall topology, and enzymatic class. At the same time a secondary shell of more weakly frustrated interactions surrounds the catalytic site itself. We evaluate the conservation of these energetic signatures in various family members of major enzyme classes, showing that local frustration is evolutionarily more conserved than the primary structure itself.


Subject(s)
Enzymes/chemistry , Models, Molecular , Protein Folding , Catalytic Domain
3.
Nucleic Acids Res ; 44(W1): W356-60, 2016 07 08.
Article in English | MEDLINE | ID: mdl-27131359

ABSTRACT

The protein frustratometer is an energy landscape theory-inspired algorithm that aims at localizing and quantifying the energetic frustration present in protein molecules. Frustration is a useful concept for analyzing proteins' biological behavior. It compares the energy distributions of the native state with respect to structural decoys. The network of minimally frustrated interactions encompasses the folding core of the molecule. Sites of high local frustration often correlate with functional regions such as binding sites and regions involved in allosteric transitions. We present here an upgraded version of a webserver that measures local frustration. The new implementation that allows the inclusion of electrostatic energy terms, important to the interactions with nucleic acids, is significantly faster than the previous version enabling the analysis of large macromolecular complexes within a user-friendly interface. The webserver is freely available at URL: http://frustratometer.qb.fcen.uba.ar.


Subject(s)
Algorithms , Nuclear Proteins/chemistry , Nucleic Acids/chemistry , Nucleosomes/chemistry , User-Computer Interface , Amino Acid Sequence , Computer Graphics , Humans , Internet , Molecular Dynamics Simulation , Nuclear Proteins/genetics , Nucleic Acids/genetics , Nucleosomes/genetics , Protein Folding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Sequence Analysis, Protein , Static Electricity , Thermodynamics
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