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Weighted Implementation of Suboptimal Paths (WISP): An Optimized Algorithm and Tool for Dynamical Network Analysis.

Van Wart AT, Durrant J, Votapka L, Amaro RE - J Chem Theory Comput (2014)

Bottom Line: Allostery can occur by way of subtle cooperation among protein residues (e.g., amino acids) even in the absence of large conformational shifts.Dynamical network analysis has been used to model this cooperation, helping to computationally explain how binding to an allosteric site can impact the behavior of a primary site many ångstroms away.To demonstrate the utility of our program, we present a case study describing the allostery of HisH-HisF, an amidotransferase from T. maritima thermotiga.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , San Diego, La Jolla, California 92093-0340, United States.

ABSTRACT
Allostery can occur by way of subtle cooperation among protein residues (e.g., amino acids) even in the absence of large conformational shifts. Dynamical network analysis has been used to model this cooperation, helping to computationally explain how binding to an allosteric site can impact the behavior of a primary site many ångstroms away. Traditionally, computational efforts have focused on the most optimal path of correlated motions leading from the allosteric to the primary active site. We present a program called Weighted Implementation of Suboptimal Paths (WISP) capable of rapidly identifying additional suboptimal pathways that may also play important roles in the transmission of allosteric signals. Aside from providing signal redundancy, suboptimal paths traverse residues that, if disrupted through pharmacological or mutational means, could modulate the allosteric regulation of important drug targets. To demonstrate the utility of our program, we present a case study describing the allostery of HisH-HisF, an amidotransferase from T. maritima thermotiga. WISP and its VMD-based graphical user interface (GUI) can be downloaded from http://nbcr.ucsd.edu/wisp.

No MeSH data available.


Related in: MedlinePlus

Node degeneracy in signalingpathways. The total number of timesa given residue participates in any of the 700 paths (i.e., node degeneracy)is shown for (A) HisF and (B) HisH. Green indicates the holo state,blue indicates the apo state, and cyan indicates an overlap. Notethat Leu50:HisF and Glu180:HisH are present in all 700 paths.
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fig5: Node degeneracy in signalingpathways. The total number of timesa given residue participates in any of the 700 paths (i.e., node degeneracy)is shown for (A) HisF and (B) HisH. Green indicates the holo state,blue indicates the apo state, and cyan indicates an overlap. Notethat Leu50:HisF and Glu180:HisH are present in all 700 paths.

Mentions: To identify protein residues critical for allosteric transmission,we counted the number of times each residue appeared in any of the700 paths associated with the apo and holo trajectories, respectively(i.e., the degeneracy of each node, Figure 5). Notably, a numberof residues had large effector-molecule-dependent shifts in degeneracy,i.e., HisF: LEU47 (shifts down), VAL69 (shifts up), ALA70 (shiftsup), ILE73 (shifts up), ASP74 (shifts up), PRO76 (shifts down), andALA97 (shifts down) and HisH: LYS181 (slight shift down) (Table 2). Importantly, these residues, which may be crucialfor the regulation of protein activity, did not all appear in theoptimal apo and holo paths and so would not have been identified hadthe suboptimal paths been ignored. Previous studies in evolutionaryconservation have shown that HisF: LEU47, VAL69, ALA70, and ILE73are partially or strongly conserved and HisF: PRO76 and ALA97 andHisH: LYS181 are strictly conserved across the entire glutamine amidotransferasefamily of enzymes.38 HisF: ASP74 is notconserved, but this amino acid is still predicted to play a role inallostery.38 Compounds that target (i.e.,selectively bind) these critical residues may serve as useful precursorsto future allosteric-modulating small molecules.


Weighted Implementation of Suboptimal Paths (WISP): An Optimized Algorithm and Tool for Dynamical Network Analysis.

Van Wart AT, Durrant J, Votapka L, Amaro RE - J Chem Theory Comput (2014)

Node degeneracy in signalingpathways. The total number of timesa given residue participates in any of the 700 paths (i.e., node degeneracy)is shown for (A) HisF and (B) HisH. Green indicates the holo state,blue indicates the apo state, and cyan indicates an overlap. Notethat Leu50:HisF and Glu180:HisH are present in all 700 paths.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3958135&req=5

fig5: Node degeneracy in signalingpathways. The total number of timesa given residue participates in any of the 700 paths (i.e., node degeneracy)is shown for (A) HisF and (B) HisH. Green indicates the holo state,blue indicates the apo state, and cyan indicates an overlap. Notethat Leu50:HisF and Glu180:HisH are present in all 700 paths.
Mentions: To identify protein residues critical for allosteric transmission,we counted the number of times each residue appeared in any of the700 paths associated with the apo and holo trajectories, respectively(i.e., the degeneracy of each node, Figure 5). Notably, a numberof residues had large effector-molecule-dependent shifts in degeneracy,i.e., HisF: LEU47 (shifts down), VAL69 (shifts up), ALA70 (shiftsup), ILE73 (shifts up), ASP74 (shifts up), PRO76 (shifts down), andALA97 (shifts down) and HisH: LYS181 (slight shift down) (Table 2). Importantly, these residues, which may be crucialfor the regulation of protein activity, did not all appear in theoptimal apo and holo paths and so would not have been identified hadthe suboptimal paths been ignored. Previous studies in evolutionaryconservation have shown that HisF: LEU47, VAL69, ALA70, and ILE73are partially or strongly conserved and HisF: PRO76 and ALA97 andHisH: LYS181 are strictly conserved across the entire glutamine amidotransferasefamily of enzymes.38 HisF: ASP74 is notconserved, but this amino acid is still predicted to play a role inallostery.38 Compounds that target (i.e.,selectively bind) these critical residues may serve as useful precursorsto future allosteric-modulating small molecules.

Bottom Line: Allostery can occur by way of subtle cooperation among protein residues (e.g., amino acids) even in the absence of large conformational shifts.Dynamical network analysis has been used to model this cooperation, helping to computationally explain how binding to an allosteric site can impact the behavior of a primary site many ångstroms away.To demonstrate the utility of our program, we present a case study describing the allostery of HisH-HisF, an amidotransferase from T. maritima thermotiga.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , San Diego, La Jolla, California 92093-0340, United States.

ABSTRACT
Allostery can occur by way of subtle cooperation among protein residues (e.g., amino acids) even in the absence of large conformational shifts. Dynamical network analysis has been used to model this cooperation, helping to computationally explain how binding to an allosteric site can impact the behavior of a primary site many ångstroms away. Traditionally, computational efforts have focused on the most optimal path of correlated motions leading from the allosteric to the primary active site. We present a program called Weighted Implementation of Suboptimal Paths (WISP) capable of rapidly identifying additional suboptimal pathways that may also play important roles in the transmission of allosteric signals. Aside from providing signal redundancy, suboptimal paths traverse residues that, if disrupted through pharmacological or mutational means, could modulate the allosteric regulation of important drug targets. To demonstrate the utility of our program, we present a case study describing the allostery of HisH-HisF, an amidotransferase from T. maritima thermotiga. WISP and its VMD-based graphical user interface (GUI) can be downloaded from http://nbcr.ucsd.edu/wisp.

No MeSH data available.


Related in: MedlinePlus