A Glance into MTHFR Deficiency at a Molecular Level
Abstract
:1. Introduction
2. Results
2.1. MTHFR and Protein-Protein Interactions
2.2. MTHFR and Protein Stability
ΔΔG (kcal/mol) | ||||||
---|---|---|---|---|---|---|
Variation | Effects | INPS3D | FoldX | PoPMuSiC2 | ISPRED4 | RSA (%) |
Catalytic Domain | ||||||
R46Q | No effect on NAD(P) affinity | −0.76 | −0.26 | −1.05 | N | 29 |
R46W | No effect on NAD(P) affinity | −0.5 | −1.04 | −0.35 | N | 29 |
R51P | −1.24 | −1.13 | −1.47 | N | 49 | |
R52Q | Reduced affinity for NAD(P) | −1.06 | 0.08 | −0.77 | N | 23 |
W59C | −1.59 | −3.58 | −2.52 | N | 2 | |
W59S | −2.67 | −3.92 | −3.3 | N | 2 | |
P66L | NAD(P) binding site | −0.46 | −4.09 | −0.01 | N | 20 |
R68G | Reduced affinity for NAD(P) NAD(P) binding site | −0.92 | −0.40 | −0.59 | N | 96 |
R82W | No effect on NAD(P) affinity | −0.66 | 0.2 | −0.81 | N | 44 |
A113T | No effect NADPH | −1.17 | −1.44 | −1.71 | N | 0 |
A116T | −0.65 | −2.29 | −1.95 | N | 0 | |
H127Y | FAD binding site | −0.18 | 1.37 | −0.33 | N | 5 |
T129N | Reduced affinity for NAD(P) FAD binding site | −1.17 | −1.37 | −0.81 | N | 7 |
C130R | No effect on NAD(P) affinity | −1.99 | −16.08 | −1.34 | N | 1 |
T139M | −0.34 | 0.83 | 0.29 | N | 18 | |
Q147P | −0.46 | −2.95 | −0.91 | N | 73 | |
G149V | −1.02 | −13.0 | −3.26 | N | 2 | |
I153M | No effect on NAD(P) affinity | −1.56 | 0.18 | −1.71 | N | 1 |
R157Q | No effect on NAD(P) affinity FAD binding site | −1.31 | −0.72 | −0.57 | N | 25 |
A175T | Reduced affinity for NAD(P) FAD binding site | −1.13 | −0.73 | −0.54 | N | 8 |
H181D | −1.79 | −2.23 | −1.5 | N | 10 | |
R183Q | No effect on NAD(P) affinity | −1.48 | −3.34 | −0.82 | N | 16 |
C193Y | −1.19 | −10.91 | −0.03 | N | 17 | |
A195V | Reduced affinity for NAD(P) FAD binding site | −0.43 | 0.39 | 0 | N | 11 |
G196D | Reduced affinity for NAD(P) | −1.08 | −3.26 | −1.18 | N | 2 |
P202T | FAD binding site | −0.73 | −1.57 | −0.16 | N | 68 |
V218L | Decreased affinity for FAD | −1.00 | −0.42 | −0.42 | N | 12 |
A222V * | Decreased affinity for FAD | −0.71 | −1.08 | −0.09 | N | 11 |
I225L | No effect on NAD(P) affinity | −1.32 | −0.57 | −1.17 | N | 0 |
T227M | −1.58 | −2.9 | −0.14 | N | 1 | |
P251L | −0.56 | 0.62 | −0.68 | N | 38 | |
V253F | Reduced affinity for NAD(P) | −0.82 | −1.26 | −1 | N | 0 |
P254S | No effect on NAD(P) affinity | −1.22 | −3.7 | −0.86 | N | 0 |
G255V | −0.55 | −2.81 | 0.33 | N | 1 | |
I256N | −3.24 | −3.27 | −2.47 | N | 1 | |
F257V | −1.34 | −1.61 | −1.83 | N | 11 | |
L323P | Substrate binding site NAD(P) binding site | −2.19 | −4.95 | −1.94 | N | 32 |
N324S | −0.77 | −3.52 | −1.92 | N | 8 | |
R325C | Substrate binding site | −0.78 | 0.41 | −0.34 | N | 43 |
L333P | −3.39 | −6.05 | −3.62 | N | 0 | |
R335C | −0.67 | −1.14 | −0.86 | N | 60 | |
Regulatory Domain | ||||||
M338T | −1.58 | −3.74 | −1.21 | N | 18 | |
W339G | −2.78 | −4.46 | −2.55 | N | 20 | |
R345C | −0.67 | −1.31 | −0.23 | N | 43 | |
P348S | Reduced affinity for NAD(P) SAH binding site | −1.19 | −3.53 | −1.16 | N | 26 |
H354Y | Reduced affinity for NAD(P) | −0.24 | −0.2 | −0.67 | N | 18 |
R357C | −1.32 | −2.3 | −1.54 | N | 5 | |
R357H | −1.28 | −1.09 | −0.29 | N | 5 | |
R363H | Reduced affinity for NAD(P) | −1.39 | −1.34 | −0.83 | N | 6 |
K372E | Reduced affinity for NAD(P) | −0.46 | 0.99 | −0.31 | N | 52 |
R377C | Reduced affinity for NAD(P) | −1.17 | −3.99 | −1.4 | N | 0 |
R377H | Reduced affinity for NAD(P) | −1.2 | −4.59 | −0.68 | N | 0 |
W381R | −1.83 | −2.29 | −1.95 | N | 14 | |
G387D | Reduced affinity for NAD(P) | −0.82 | −3.35 | −1.31 | I | 33 |
G390D | −0.88 | −2.23 | 0.13 | N | 64 | |
W421S | Reduced affinity for NAD(P) | −3.07 | −6.97 | −4 | N | 1 |
E429A * | −0.13 | −0.79 | 0.2 | N | 50 | |
F435S | −3.45 | −5.56 | −2.94 | N | 1 | |
S440L | 0.03 | 2.15 | −0.55 | N | 25 | |
Y506D | Reduced affinity for NAD(P) | −1.77 | −5.1 | −3.16 | I | 61 |
Y512C | −1.94 | −4.31 | −2.18 | N | 2 | |
R535Q | −0.79 | −1.61 | −0.77 | N | 25 | |
R535W | 0.07 | −1.39 | −0.26 | N | 25 | |
V536F | Reduced affinity for NAD(P) | −1.38 | −3.21 | −0.6 | N | 1 |
P572L | Reduced affinity for NAD(P) | −0.43 | −7.32 | −0.09 | N | 0 |
V574G | Reduced affinity for NAD(P) | −3.32 | −4.13 | −3.47 | N | 1 |
V575G | Reduced affinity for NAD(P) | −3.64 | −4.06 | −3.07 | N | 8 |
E586K | −0.8 | −5.23 | −0.99 | N | 1 | |
L598P | Reduced affinity for NAD(P) | −2.49 | −7.34 | −2.68 | N | 22 |
S603C | −1.03 | −1.81 | −0.7 | N | 15 | |
L628P | Reduced affinity for NAD(P) | −0.83 | −4.47 | −2.25 | I | 57 |
M338T | −1.58 | −3.74 | −1.21 | N | 18 |
2.3. MTHFR Deficiency and Its Structural Model
3. Materials and Methods
3.1. Characterization of Protein Surface and Annotation of Protein-Protein Interaction Sites
3.2. Prediction of ∆∆G Changes upon Single Residue Variation
3.3. Pfam-Like Model of the Regulatory Domain
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Savojardo, C.; Babbi, G.; Baldazzi, D.; Martelli, P.L.; Casadio, R. A Glance into MTHFR Deficiency at a Molecular Level. Int. J. Mol. Sci. 2022, 23, 167. https://doi.org/10.3390/ijms23010167
Savojardo C, Babbi G, Baldazzi D, Martelli PL, Casadio R. A Glance into MTHFR Deficiency at a Molecular Level. International Journal of Molecular Sciences. 2022; 23(1):167. https://doi.org/10.3390/ijms23010167
Chicago/Turabian StyleSavojardo, Castrense, Giulia Babbi, Davide Baldazzi, Pier Luigi Martelli, and Rita Casadio. 2022. "A Glance into MTHFR Deficiency at a Molecular Level" International Journal of Molecular Sciences 23, no. 1: 167. https://doi.org/10.3390/ijms23010167