Year: 2019
Type: article
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.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G1072792134, Termodinámica y evolución de proteínas repetitivas, G184053464, G3701106356, Conceptual Aspects of Protein Folding, LIFE IS ELECTRIC. THE ELECTRONIC CIRCUITRY IS CATALYZED BY A SMALL SUBSET OF PROTEINS THAT FUNCTION AS SOPHISTICATED NANOMACHINES. CURRENTLY VERY LITTLE IS KNOWN ABOUT THE ORIGIN OF PROTEINS ON EARTH AND THEIR EVOLUTION IN EARLY MICROBIAL LIFE. TO FILL THIS KNOWLEDGE GAP THE ENIGMA RESEARCH PROGRAM WILL CARRY OUT EXPERIMENTAL BIOINFORMATIC DATA-DRIVEN ABDUCTIVE STUDIES TO EXPLORE THE ORIGIN OF CATALYSIS THE EVOLUTION OF PROTEIN STRUCTURES IN MICROBIAL ANCESTORS AND THE CO-EVOLUTION OF PROTEINS AND THE GEOSPHERE THROUGH GEOLOGIC TIME. ENIGMA HAS THREE INTEGRATED RESEARCH THEMES FOCUSED ON UNDERSTANDING THE EVOLUTION OF PROTEINS INVOLVED IN ELECTRON TRANSFER AND ENERGY GENERATION. THEME 1 WILL INVESTIGATE THE SYNTHESIS AND FUNCTION OF METALLOPROTEINS IN PREBIOTIC SYSTEMS. EXTANT MICROBIAL PROTEINS WILL BE ANALYZED TO IDENTIFY THE SIMPLEST STRUCTURES THAT CAN PERFORM ELECTRON TRANSFER REACTIONS. USING DE NOVO COMPUTATIONAL PROTEIN DESIGN SMALL PEPTIDES WILL BE SYNTHESIZED AND CHARACTERIZED TO ELUCIDATE THE EARLIEST BIOCHEMICAL REACTIONS IN THE ORIGIN OF LIFE. THEME 2 WILL EXAMINE THE EMERGENT COMPLEXITY OF METALLOPROTEINS IN MICROBIAL ANCESTORS. NEW COMPUTATIONAL METHODS LINKING PROTEIN STRUCTURE AND PHYLOGENY WILL BE DEVELOPED TO STUDY THE EVOLUTION OF METAL BINDING LIGANDS IN PROTEINS. A STRUCTURAL ALIGNMENT-BASED HOMOLOGY APPROACH WILL BE USED TO IDENTIFY THE OLDEST STRUCTURES IN PROTEINS AND TO TRACE THE EARLY EVOLUTION OF METAL BINDING FOLDS. THEME 3 WILL EXPLORE THE CO-EVOLUTION OF PROTEINS AND THE GEOSPHERE. DEEP-TIME DATA ON THE NATURE AND DISTRIBUTION OF REDOX-SENSITIVE ELEMENTS IN ROCKS AND MINERALS WILL BE INTEGRATED WITH PROTEIN STRUCTURAL DATA IN THE PROTEIN DATA BANK. MINERALOGICAL DATA (E.G. MINERAL COMPOSITION SOLUBILITY AND AGE) WILL BE INCORPORATED INTO GEOCHEMICAL MODELS TO CONSTRAIN THE BIOAVAILABILITY OF METALS OVER GEOLOGIC TIME AND METAL BIOAVAILABILITY DURING ARCHEAN AND PROTEROZOIC ERAS WILL USED TO DATE SPECIFIC POSITIONS IN THE EVOLUTIONARY TREE CONSTRUCTED IN THEME 2. THE THREE ENIGMA RESEARCH THEMES ARE DIRECTLY RELEVANT TO THE MAJOR TOPICS SYNTHESIS AND FUNCTION OF MACROMOLECULES IN THE ORIGIN OF LIFE EARLY LIFE AND INCREASING COMPLEXITY AND CO-EVOLUTION OF LIFE AND THE PHYSICAL ENVIRONMENT IDENTIFIED IN THE 2015 ASTROBIOLOGY SCIENCE STRATEGY. FURTHERMORE THE ENIGMA PROGRAM COMPLEMENTS THE NAI CAN 7 TEAMS ON EXPERIMENTAL MICROBIAL GENOMICS (GEORGIA TECH) AND LIFE ON A DYNAMIC EARLY EARTH (UC RIVERSIDE). THE RESULTS OF THE ENIGMA RESEARCH PROGRAM WILL HELP THE NAI ANSWER A CENTRAL QUESTION IN ASTROBIOLOGY: HOW DID PROTEINS EVOLVE TO BECOME THE CATALYSTS OF LIFE ON EARTH?
OpenAlex ID: W2913365007