ArticleBiochemistry2015
Interpretation of pH-activity profiles for acid-base catalysis from molecular simulations.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- A Multi-Scale Computational Framework for Anti-Persister Tuberculosis Drug Discovery.Chemical biology & drug design · 2026Review
- Adding the AMBER 14SB Force Field to the Stochastic Titration CpHMD Method.Journal of chemical theory and computation · 2025Article
- Investigating the Roles of Active Site Residues inACS bio & med chem Au · 2023Article
- Catalytic mechanism and pH dependence of a methyltransferase ribozyme (MTR1) from computational enzymology.Nucleic acids research · 2023Article
- Redesigning plant specialized metabolism with supervised machine learning using publicly available reactome data.Computational and structural biotechnology journal · 2023Review
- Shifting the pH Optima of (International journal of molecular sciences · 2022Article
- Extending the Stochastic Titration CpHMD to CHARMM36m.The journal of physical chemistry. B · 2022Article
- Two-Metal-Ion Catalysis: Inhibition of DNA Polymerase Activity by a Third Divalent Metal Ion.Frontiers in molecular biosciences · 2022Review
- Beyond the Plateau: pL Dependence of Proton Inventories as a Tool for Studying Ribozyme and Ribonuclease Catalysis.Biochemistry · 2021Article
- Scalable molecular dynamics on CPU and GPU architectures with NAMD.The Journal of chemical physics · 2020Article
- Dynamical ensemble of the active state and transition state mimic for the RNA-cleaving 8-17 DNAzyme in solution.Nucleic acids research · 2019Article
- Cleaning Up Mechanistic Debris Generated by Twister Ribozymes Using Computational RNA Enzymology.ACS catalysis · 2019Article
- GPU-Accelerated Molecular Dynamics and Free Energy Methods in Amber18: Performance Enhancements and New Features.Journal of chemical information and modeling · 2018Article
- Reservoir pH replica exchange.The Journal of chemical physics · 2018Article
- Phosphodiester models for cleavage of nucleic acids.Beilstein journal of organic chemistry · 2018Review
- Ribozyme Catalysis with a Twist: Active State of the Twister Ribozyme in Solution Predicted from Molecular Simulation.Journal of the American Chemical Society · 2016Article
- Sequence comparison, molecular modeling, and network analysis predict structural diversity in cysteine proteases from the Cape sundew, Drosera capensis.Computational and structural biotechnology journal · 2016Article
- Continuum Electrostatics Approaches to Calculating pKas and Ems in Proteins.Methods in enzymology · 2016Review
- Computation of pH-dependent binding free energies.Biopolymers · 2016Review
- Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria.PLoS computational biology · 2015Article
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5 authors.
Funding
Abstract
The measurement of reaction rate as a function of pH provides essential information about mechanism. These rates are sensitive to the pK(a) values of amino acids directly involved in catalysis that are often shifted by the enzyme active site environment. Experimentally observed pH-rate profiles are usually interpreted using simple kinetic models that allow estimation of "apparent pK(a)" values of presumed general acid and base catalysts. One of the underlying assumptions in these models is that the protonation states are uncorrelated. In this work, we introduce the use of constant pH molecular dynamics simulations in explicit solvent (CpHMD) with replica exchange in the pH-dimension (pH-REMD) as a tool to aid in the interpretation of pH-activity data of enzymes and to test the validity of different kinetic models. We apply the methods to RNase A, a prototype acid-base catalyst, to predict the macroscopic and microscopic pK(a) values, as well as the shape of the pH-rate profile. Results for apo and cCMP-bound RNase A agree well with available experimental data and suggest that deprotonation of the general acid and protonation of the general base are not strongly coupled in transphosphorylation and hydrolysis steps. Stronger coupling, however, is predicted for the Lys41 and His119 protonation states in apo RNase A, leading to the requirement for a microscopic kinetic model. This type of analysis may be important for other catalytic systems where the active forms of the implicated general acid and base are oppositely charged and more highly correlated. These results suggest a new way for CpHMD/pH-REMD simulations to bridge the gap with experiments to provide a molecular-level interpretation of pH-activity data in studies of enzyme mechanisms.
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