PMID- 34351775
OWN - NLM
STAT- MEDLINE
DCOM- 20211019
LR  - 20220531
IS  - 1520-5207 (Electronic)
IS  - 1520-5207 (Linking)
VI  - 125
IP  - 32
DP  - 2021 Aug 19
TI  - pH Effects and Cooperativity among Key Titratable Residues for Escherichia coli 
      Glycinamide Ribonucleotide Transformylase.
PG  - 9168-9185
LID - 10.1021/acs.jpcb.1c04668 [doi]
AB  - Human glycinamide ribonucleotide transformylase (GAR Tfase) is a regulatory 
      enzyme in the de novo purine biosynthesis pathway that has been extensively 
      studied as an anticancer target. To some extent, inhibition of GAR Tfase 
      selectively targets cancer cells over normal cells and inhibits purine formation 
      and DNA replication. In this study, we investigated E. coli GAR Tfase, which 
      shares high sequence similarity with the human GAR Tfase, and most functional 
      residues are conserved. Herein, we aim to predict the pH-activity curve through a 
      computational approach. We carried out pH-replica exchange molecular dynamics 
      (pH-REMD) simulations to investigate pH-dependent functions such as structural 
      changes, ligand binding, and catalytic activity. To compute the pH-activity 
      curve, we identified the catalytic residues in specific protonation states, 
      referred to as the catalytic competent protonation states (CCPS), which maintain 
      the structure, keep ligands bound, and facilitate catalysis. Our computed 
      population of CCPS with respect to pH matches well with the experimental 
      pH-activity curve. To compute the microscopic pK(a) values in the catalytically 
      active conformation, we devised a thermodynamic model that considers the coupling 
      between protonation states of CCPS residues and conformational states. These 
      results allow us to correctly identify the general acid and base catalysts and 
      interpret the pH-activity curve at an atomistic level.
FAU - Gupta, Pancham Lal
AU  - Gupta PL
AD  - Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, 
      Florida 32611-7200, United States.
FAU - Smith, Justin S
AU  - Smith JS
AD  - Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New 
      Mexico 87545, United States.
FAU - Roitberg, Adrian E
AU  - Roitberg AE
AUID- ORCID: 0000-0003-3963-8784
AD  - Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, 
      Florida 32611-7200, United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210805
PL  - United States
TA  - J Phys Chem B
JT  - The journal of physical chemistry. B
JID - 101157530
RN  - EC 2.1.2.- (Hydroxymethyl and Formyl Transferases)
RN  - EC 2.1.2.2 (Phosphoribosylglycinamide Formyltransferase)
SB  - IM
MH  - *Escherichia coli/genetics
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - *Hydroxymethyl and Formyl Transferases
MH  - Molecular Conformation
MH  - Phosphoribosylglycinamide Formyltransferase/genetics
EDAT- 2021/08/06 06:00
MHDA- 2021/10/21 06:00
CRDT- 2021/08/05 17:12
PHST- 2021/08/06 06:00 [pubmed]
PHST- 2021/10/21 06:00 [medline]
PHST- 2021/08/05 17:12 [entrez]
AID - 10.1021/acs.jpcb.1c04668 [doi]
PST - ppublish
SO  - J Phys Chem B. 2021 Aug 19;125(32):9168-9185. doi: 10.1021/acs.jpcb.1c04668. Epub 
      2021 Aug 5.