Molecular dynamics study of interaction and substrate channeling between neuron‐specific enolase and B‐type phosphoglycerate mutase

Abstract

Phosphoglycerate mutase (PGM) and enolase are consecutive enzymes in the glycolytic pathway. We used molecular dynamics simulation to examine the interaction of human B-type PGM (dPGM-B) and neuron-specific enolase (NSE). Specifically, we studied the interactions of 31 orientations of these enzymes by means of the effective energy function implicit solvation method. Interactions between active regions of the enzymes occurred preferentially, although the strongest interactions appeared to be between the back side of NSE and the active regions of dPGM-B. Cleavage of 2PG from dPGM-B was investigated, and the Ser(14)-Leu(30) loop of dPGM-B is suggested as a cleavage site and, likely, another entrance site of a ligand. Substrate channeling between the enzymes was observed when NSE with its active regions Leu(11)-Asn(16), Arg(49)-Lys(59), and Gly(155)-Ala(158) covered the Ser(14)-Leu(30) loop of dPGM-B. Analyses of the results make us believe that the channeling between PGM and enolase "benefits" from weak interaction. The probability of formation of channeling favorable complex is estimated to be up to 5%, while functional interaction between NSE and dPGM-B might be as high as 20%. NSE and dPGM-B functional interaction seems not to be isotype specific.

Complex formation dynamics of native and mutated pyrin's B30.2 domain with caspase‐1

“…The selected simulation time was sufficient to achieve equilibrium state in the modeled systems, which follows from the analysis of the interaction energy oscillation. To evaluate binding free energy of B30.2 domain native and mutant structures with caspase‐1 a 10 Å nonbond list cutoff together with a 7–9 Å switching function, a linear distance‐dependent dielectric constant and a frictional coefficient of 5 for Langevin molecular dynamics with Leapfrog integrator were used for electrostatic and van der Waals forces, respectively …”

“…To evaluate binding free energy of B30.2 domain native and mutant structures with caspase-1 a 10 Å nonbond list cutoff together with a 7-9 Å switching function, a linear distance-dependent dielectric constant and a frictional coefficient of 5 for Langevin molecular dynamics with Leapfrog integrator were used for electrostatic and van der Waals forces, respectively. 30 Visualization and comparative analysis of the native and mutated tertiary structures of the B30.2 domains and their complexes with caspase-1 were performed, using the VMD 1.9.2 software. 31 VMD 1.9.2 also provides possibility to calculate the root-mean-square deviation (RMSD) between the native and mutated models of B30.2 tertiary structure.…”

The Role of Protein Loops and Linkers in Conformational Dynamics and Allostery

“…[154][155][156] Enolases or aldolases feature loop movements that allow the catalytic residues to be oriented in the proper position for catalysis. 65,[157][158][159][160] In a similar way, protein tyrosine phosphatases (PTPs) 161 are characterized by a WPD loop that includes a catalytic aspartate (Figure 8). This loop closes over the active site upon binding of the substrate and loop closure allows the correct positioning of functional residues around the ligand and protect the site from bulk solvent during catalysis.…”

Development of force field parameters for oxyluciferin on its electronic ground and excited states

“…With the development of modern computer technologies, the method is now applicable even for very large molecular systems [5,6]. Biomolecules such as protein complexes and lipid layers are typical examples of large systems where MD is actively applied in recent studies for obtaining detailed pictures of molecular events, such as protein conformational dynamics [7][8][9] or ligand-enzyme interactions [10][11][12]. With the exception of ab initio direct dynamics for rather small molecules, classical MD simulation is intrinsically an empirical approach, where the dynamical changes of the target systems are governed by mathematically formulated model potential energy surfaces (force fields) [13,14].…”