Binomlabs
Analysis of neutral and oncological mutations by calculating thermodynamic characteristics.
The correlations were performed on real solutions in a biochemical laboratory.
For the negative set, protein variants that were never found (693 variants) or found only once( 323 variants) in human cancer have been selected (no_cancer p53 variants)
[TP53_PROF:a machine learning model to predict impact of missense mutations inTP53]
[TP53_PROF:a machine learning model to predict impact of missense mutations inTP53]
A diagram of the calculated values for each set of p53 protein mutations, which we will further analyze.
Cancer-related Mutations
TP53 mutation data was aggregated from multiple studies
Effects of Common Cancer Mutations on Stability
Silent and oncological mutations in p53
Heat map of reliable electrostatic interaction energy between pairwise amino acid residues of the p53 monomer
The difference in the calculations obtained for the Positive and Negative set of p53 mutations
Start calculate Effects of Single Mutations
on Protein Stability right now!
For Monomer and Dimer Protein only
on Protein Stability right now!
For Monomer and Dimer Protein only
You can either regularly use the server services and
stay in touch with specialists, or cancel them at any time.
- Collection of materials,
- Technical assignment,
- Calculations up to N variants,
- Obtaining data
- Data processing,
- Sorting,
- Plotting graphs,
- Dependencies,
- Explanatory note for each calculation
- Starting with 50 mutations, machine learning methods will be applied.
If you need 200 mutations or more, then the price increases proportionally with a decreasing coefficient, i.e. the calculation of one mutation when ordering 200 mutations will be cheaper than the cost of 1 mutation when ordering 10 mutations.
Second Set
Average amount up to 20
$70
Calculations up to 20 variants.
Explanatory notes for each calculation
Explanatory notes for each calculation
Order now
Second Set
Average amount up to 50
$130
Calculations up to 50 variants.
Explanatory notes for each calculation
Explanatory notes for each calculation
Order now
Special set
Larch amount up to 100
$249
Calculations up to 100 variants.
Explanatory notes for each calculation
Explanatory notes for each calculation
Order now
Lock-and-Key:
An Entropy-Dominated Binding Process
An Entropy-Dominated Binding Process
Therefore, for the lock-and-key binding to proceed, the solvent entropy gain should be large enough to overcompensate for not only the positive enthalpy change arising from the desolvation process, but also the negative entropy change caused by the loss of rotational and translational motions of the ligand.
Indeed, the negative enthalpy change arising
from the favorable interactions (such as van der Waals forces, hydrogen bonding, electrostatic, and dipole–dipole interactions) can also contribute to the lowering of the system’s free energy, but the solvent entropy gain arising from the displacement of the water molecules plays a dominant role in lowering the free energy. Therefore, it is reasonable to conclude that the lock-and-key binding is a entropy-dominated process.
[Insights into Protein–Ligand Interactions: Mechanisms, Models, and Methods]
[Some Binding-Related Drug Properties are Dependent on Thermodynamic Signature]
Thermodynamic profiles for three pairs of HIV-1 proteinase inhibitors that vary by only a single group: (a) KNI-10033-KNI-10075 pair within which an apolar group thioether on KNI-10033 is replaced by a polar group sulfonyl to form KNI-10075; (b) KNI-10052-KNI-10054 pair within which an apolar methyl group is replaced by a polar hydroxyl group; and (c) KNI-10046-KNI-10030 pair within which a hydrogen atom on the former is replaced by an apolar methyl group to form the latter. The binding free energy (∆G), enthalpy (∆H), and entropy (T∆S) are shown
[Freire, E. The binding thermodynamics of drug candidate. In Thermodynamics and Kinetics of Drug Binding; Keserü, G.M., Swinney, D.C., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2015; pp. 1–13.]
[Lafont, V.; Armstrong, A.A.; Ohtaka, H.; Kiso, Y.; Mario Amzel, L.; Freire, E. Compensating enthalpic and entropic changes hinder binding affinity optimization. Chem. Biol. Drug Des. 2007, 69, 413–422.]
[Kawasaki, Y.; Freire, E. Finding a better path to drug selectivity. Drug Discov. Today 2011, 16, 985–990.]
NBD-556 is a competitive inhibitor of CD4 characterized by a binding affinity of 3.7 μM. Despite the small size, NBD-556 binds with a thermodynamic signature that resembles that of CD4 (ΔH = -24.5 kcal/mol, -TΔS = 17.1 kcal/mol at 25 °C
dH, kcal/mol
dH, kcal/mol
-TΔS, kcal/mol
-TΔS, kcal/mol
The thermodynamic signatures of sCD4 and NBD-556 at 25°C. The large conformational structuring of gp120 triggered by CD4 binding is reflected in a thermodynamic signature characterized by an unusually large favorable change in enthalpy and a very large unfavorable entropy change. Except for a lower affinity, the binding of NBD-556 to gp120 is also associated with enthalpy and entropy changes similar to those observed for CD4. ΔG is represented by blue bars, ΔH by green bars and -TΔS by red bars.
Free energy calculations of protein-ligand complexes
Fechner Correlation
The FECHNER CORRELATION command calculates the Fechner signs correlation coefficient between all the pairs of variables. Fechner correlation coefficient is used to check relationship for small samples.
How To
Run: STATISTICS->NONPARAMETRIC STATISTICS-> FECHNER CORRELATION...
Select the variables you want to correlate.
Pairwise deletion is default for missing values removal (use the MISSING VALUES option in the PREFERENCES window to force casewise deletion).
Results:
Matrix with Fechner correlation coefficients between each pair of variables is calculated.
Fechner correlation coefficient is defined by
Run: STATISTICS->NONPARAMETRIC STATISTICS-> FECHNER CORRELATION...
Select the variables you want to correlate.
Pairwise deletion is default for missing values removal (use the MISSING VALUES option in the PREFERENCES window to force casewise deletion).
Results:
Matrix with Fechner correlation coefficients between each pair of variables is calculated.
Fechner correlation coefficient is defined by
Negative Set of p53 mutations
p.A119P,p.A119S, p.A129G, p.A129P, p.A129S, p.A138G, p.A189S, p.C124F, p.C124W, p.C182F, p.C229G, p.C229W, p.D148A, p.D148V, p.D184A, p.D184E, p.D184V, p.D186A, p.D186E, p.D186Y p.D207A, p.D207V p.E171A, p.E171V, p.E180A, p.E180V, p.E198A, p.E198V, p.E224Q, p.E287A, ,p.F109Y, p.F113Y, p.F134Y, p.F212C, p.G108A, p.G108C, p.G112A, p.G112C, p.G112R, p.G112V, p.G117A, p.G117V, p.G117W, p.G154A, p.G154R, p.G187A, p.G226C, p.G262A, p.G262C p.G262R, p.G279A, p.H115D, p.H115L, p.H115N, p.H115P, p.H115Q, p.H115R p.H168Q, p.H178L, p.H214N, p.H233N, p.I162L, p.I195L, p.I195V, p.I255L, p.K101I, p.K101N, p.K101Q, p.K101T, p.K120T, p.L111V, p.L114F, p.L114M, p.L114S, p.L114V, p.L114W, p.L137R, p.L188Q, p.L188R, p.L201M, p.L201W, p.L206F, p.L206M, p.L206V, p.L206W, p.L252R, p.L257M, p.L264P, p.L264Q p.L264V, p.L265V, p.M169L, p.S106T, p.S116A, p.S116T, p.S116Y, p.S121A, p.S121C, p.S121T, p.S121Y, p.S127A, p.S149A, p.S149C, p.S183A, p.S183T, p.S185C, p.S185T, p.S227A, p.S227Y, p.S261I, p.T102N, p.T102P, p.T118K, p.T118P, p.T118R, p.T118S, p.T123N p.T123P, p.T123S, p.T125S, p.T140N, p.T150S, p.T170K, p.T256R, p.T284R, p.V122E, p.V122G, p.V122M, p.V147L, p.V203G, p.V225L, p.Y103C, p.Y103D, p.Y103F, p.Y103H, p.Y103N, p.Y103S, p.Y107F, p.Y107N, p.Y107S
p.A119P,p.A119S, p.A129G, p.A129P, p.A129S, p.A138G, p.A189S, p.C124F, p.C124W, p.C182F, p.C229G, p.C229W, p.D148A, p.D148V, p.D184A, p.D184E, p.D184V, p.D186A, p.D186E, p.D186Y p.D207A, p.D207V p.E171A, p.E171V, p.E180A, p.E180V, p.E198A, p.E198V, p.E224Q, p.E287A, ,p.F109Y, p.F113Y, p.F134Y, p.F212C, p.G108A, p.G108C, p.G112A, p.G112C, p.G112R, p.G112V, p.G117A, p.G117V, p.G117W, p.G154A, p.G154R, p.G187A, p.G226C, p.G262A, p.G262C p.G262R, p.G279A, p.H115D, p.H115L, p.H115N, p.H115P, p.H115Q, p.H115R p.H168Q, p.H178L, p.H214N, p.H233N, p.I162L, p.I195L, p.I195V, p.I255L, p.K101I, p.K101N, p.K101Q, p.K101T, p.K120T, p.L111V, p.L114F, p.L114M, p.L114S, p.L114V, p.L114W, p.L137R, p.L188Q, p.L188R, p.L201M, p.L201W, p.L206F, p.L206M, p.L206V, p.L206W, p.L252R, p.L257M, p.L264P, p.L264Q p.L264V, p.L265V, p.M169L, p.S106T, p.S116A, p.S116T, p.S116Y, p.S121A, p.S121C, p.S121T, p.S121Y, p.S127A, p.S149A, p.S149C, p.S183A, p.S183T, p.S185C, p.S185T, p.S227A, p.S227Y, p.S261I, p.T102N, p.T102P, p.T118K, p.T118P, p.T118R, p.T118S, p.T123N p.T123P, p.T123S, p.T125S, p.T140N, p.T150S, p.T170K, p.T256R, p.T284R, p.V122E, p.V122G, p.V122M, p.V147L, p.V203G, p.V225L, p.Y103C, p.Y103D, p.Y103F, p.Y103H, p.Y103N, p.Y103S, p.Y107F, p.Y107N, p.Y107S
Positive Set of p53 mutations
p.A138V, p.A159P, p.A159V, p.A161S, p.A161T, p.A276D, p.A276G, p.A276P, p.C124G, p.C135F, p.C135R, pC135S, p.C135W, p.C135Y, p.C141G, p.C141R, p.C141W, p.C141Y, p.C176F, p.C176G, p.C176R, p.C176W, p.C176Y, p.C238F, p.C238R, p.C238Y, p.C242F, p.C242G, p.C242S, p.C242Y, p.C275F, p.C275G, p.C275R, p.C275W, p.C275Y, p.C277F, p.C277Y, p.D259V, p.D259Y, p.D281E, p.D281H, p.D281N, p.D281V, p.D281Y, p.E180K, p.E224D, p.E258A, p.E258K, p.E258Q, p.E271K, p.E271V, p.E285K,p.E285V, p.E286A, p.E286G, p.E286K, p.E286Q, p.E286V, p.E287D, p.F109C, p.F109V, p.F113C, p.F113V, p.F134C, p.F134L, p.F134V, p.F270C, p.F270L, p.F270S, p.G105C, p.G105D, p.G105V, p.G154V, p.G199V, p.G244C, p.G244D, p.G244S, p.G244V, p.G245C, p.G245D, p.G245R, p.G245S, p.G245V, p.G262V, p.G266E, .G266R, p.G266V, p.G279E
p.A138V, p.A159P, p.A159V, p.A161S, p.A161T, p.A276D, p.A276G, p.A276P, p.C124G, p.C135F, p.C135R, pC135S, p.C135W, p.C135Y, p.C141G, p.C141R, p.C141W, p.C141Y, p.C176F, p.C176G, p.C176R, p.C176W, p.C176Y, p.C238F, p.C238R, p.C238Y, p.C242F, p.C242G, p.C242S, p.C242Y, p.C275F, p.C275G, p.C275R, p.C275W, p.C275Y, p.C277F, p.C277Y, p.D259V, p.D259Y, p.D281E, p.D281H, p.D281N, p.D281V, p.D281Y, p.E180K, p.E224D, p.E258A, p.E258K, p.E258Q, p.E271K, p.E271V, p.E285K,p.E285V, p.E286A, p.E286G, p.E286K, p.E286Q, p.E286V, p.E287D, p.F109C, p.F109V, p.F113C, p.F113V, p.F134C, p.F134L, p.F134V, p.F270C, p.F270L, p.F270S, p.G105C, p.G105D, p.G105V, p.G154V, p.G199V, p.G244C, p.G244D, p.G244S, p.G244V, p.G245C, p.G245D, p.G245R, p.G245S, p.G245V, p.G262V, p.G266E, .G266R, p.G266V, p.G279E
The fact is that the yi values for Negative Set practically coincide with the obtained average value; as a result of the difference between the average and yi values, we get a very small value tending to zero.
Neutral Mutations
Oncological mutations
WOW! affect
Difference in calculated characteristics for Positive and Negative sets of P53 protein mutations.
To determine the correlation coefficient, we use Boolean variables and the Fechner coefficient.
rb(integr) is a Fechner coefficient
rb(integr) is a Fechner coefficient
enthalpy change
N1-N60
N1-N60
Negative set
Negative set
Positive set
Positive set
Positive set
Negative set
N53-N140
N2-N89
p.A119P
p.A119S
p.A129G
p.A129P
p.A129S
p.A138G
p.A189S
p.C124F
p.C124W
p.C182F
p.C229G
p.C229W
p.D148A
p.D148V
p.D184A
p.D184E
p.D184V
p.D186A
p.D186E
p.D186Y
p.D207A
p.D207V
p.E171A
p.E171V
p.E180A
p.E180V
p.E198A
p.E198V
p.E224Q
p.E287A
p.F109Y
p.F113Y
p.F134Y
p.F212C
p.G108A
p.G108C
p.G112A
p.G112C
p.G112R
p.G112V
p.G117A
p.G117V
p.G117W
p.G154A
p.G154R
p.G187A
p.G226C
p.G262A
p.G262C
p.G262R
p.G279A
p.H115D
p.H115L
p.H115N
p.H115P
p.H115Q
p.H115R
p.H168Q
p.H178L
p.H214N
p.A119S
p.A129G
p.A129P
p.A129S
p.A138G
p.A189S
p.C124F
p.C124W
p.C182F
p.C229G
p.C229W
p.D148A
p.D148V
p.D184A
p.D184E
p.D184V
p.D186A
p.D186E
p.D186Y
p.D207A
p.D207V
p.E171A
p.E171V
p.E180A
p.E180V
p.E198A
p.E198V
p.E224Q
p.E287A
p.F109Y
p.F113Y
p.F134Y
p.F212C
p.G108A
p.G108C
p.G112A
p.G112C
p.G112R
p.G112V
p.G117A
p.G117V
p.G117W
p.G154A
p.G154R
p.G187A
p.G226C
p.G262A
p.G262C
p.G262R
p.G279A
p.H115D
p.H115L
p.H115N
p.H115P
p.H115Q
p.H115R
p.H168Q
p.H178L
p.H214N
0.73993787
0.73993397
0.7399646
0.73995984
0.73995537
0.73985441
0.7399354
0.7375981
0.73758668
0.73957824
0.73991268
0.73990698
0.73998011
0.73997562
0.74010023
0.74000325
0.73998995
0.74002283
0.74000103
0.73997485
0.74000402
0.73997575
0.74002357
0.73997244
0.74015927
0.73999621
0.74005368
0.73997331
0.74003208
0.73998698
0.73999584
0.73997822
0.7399458
0.74006543
0.73999537
0.74001586
0.74005163
0.74015792
0.74014309
0.73999474
0.74011601
0.74000749
0.74000731
0.74000035
0.74007487
0.74001805
0.74003
0.74
0.74002
0.74008
0.74007
0.74
0.73998
0.73999
0.73998
0.74007
0.74013
0.74006
0.74008
0.73999
0.73993397
0.7399646
0.73995984
0.73995537
0.73985441
0.7399354
0.7375981
0.73758668
0.73957824
0.73991268
0.73990698
0.73998011
0.73997562
0.74010023
0.74000325
0.73998995
0.74002283
0.74000103
0.73997485
0.74000402
0.73997575
0.74002357
0.73997244
0.74015927
0.73999621
0.74005368
0.73997331
0.74003208
0.73998698
0.73999584
0.73997822
0.7399458
0.74006543
0.73999537
0.74001586
0.74005163
0.74015792
0.74014309
0.73999474
0.74011601
0.74000749
0.74000731
0.74000035
0.74007487
0.74001805
0.74003
0.74
0.74002
0.74008
0.74007
0.74
0.73998
0.73999
0.73998
0.74007
0.74013
0.74006
0.74008
0.73999
p.A138V
p.A159P
p.A159V
p.A161S
p.A161T
p.A276D
p.A276G
p.A276P
p.C124G
p.C135F
p.C135R
p.C135S
p.C135W
p.C135Y
p.C141G
p.C141R
p.C141W
p.C141Y
p.C176F
p.C176G
p.C176R
p.C176W
p.C176Y
p.C238F
p.C238R
p.C238Y
p.C242F
p.C242G
p.C242S
p.C242Y
p.C275F
p.C275G
p.C275R
p.C275W
p.C275Y
p.C277F
p.C277Y
p.D259V
p.D259Y
p.D281E
p.D281H
p.D281N
p.D281V
p.D281Y
p.E180K
p.E224D
p.E258A
p.E258K
p.E258Q
p.E271K
p.E271V
p.E285K
p.E285V
p.E286A
p.E286G
p.E286K
p.E286Q
p.E286V
p.E287D
p.F109C
p.A159P
p.A159V
p.A161S
p.A161T
p.A276D
p.A276G
p.A276P
p.C124G
p.C135F
p.C135R
p.C135S
p.C135W
p.C135Y
p.C141G
p.C141R
p.C141W
p.C141Y
p.C176F
p.C176G
p.C176R
p.C176W
p.C176Y
p.C238F
p.C238R
p.C238Y
p.C242F
p.C242G
p.C242S
p.C242Y
p.C275F
p.C275G
p.C275R
p.C275W
p.C275Y
p.C277F
p.C277Y
p.D259V
p.D259Y
p.D281E
p.D281H
p.D281N
p.D281V
p.D281Y
p.E180K
p.E224D
p.E258A
p.E258K
p.E258Q
p.E271K
p.E271V
p.E285K
p.E285V
p.E286A
p.E286G
p.E286K
p.E286Q
p.E286V
p.E287D
p.F109C
0.73979859
0.73992935
0.73992999
0.73990309
0.73991134
0.739866
0.73989952
0.7398477
0.73790811
0.73676158
0.73993565
0.73758584
0.73644711
0.73674552
0.73650341
0.73801977
0.73835483
0.73771861
0.73755947
0.73683127
0.73725951
0.73756511
0.73681525
0.73657199
0.73682142
0.73757876
0.73656484
0.73762472
0.73793314
0.73740206
0.73744179
0.73944582
0.73950486
0.73972086
0.73944381
0.73941679
0.73973285
0.73972298
0.73997548
0.73997854
0.73998977
0.73998112
0.73998263
0.73997477
0.73997529
0.73999009
0.7399824
0.74008994
0.74003253
0.7402447
0.73997668
0.74017278
0.73997055
0.74000908
0.73997871
0.74014231
0.74005099
0.73996981
0.73998965
0.74006329
0.73992935
0.73992999
0.73990309
0.73991134
0.739866
0.73989952
0.7398477
0.73790811
0.73676158
0.73993565
0.73758584
0.73644711
0.73674552
0.73650341
0.73801977
0.73835483
0.73771861
0.73755947
0.73683127
0.73725951
0.73756511
0.73681525
0.73657199
0.73682142
0.73757876
0.73656484
0.73762472
0.73793314
0.73740206
0.73744179
0.73944582
0.73950486
0.73972086
0.73944381
0.73941679
0.73973285
0.73972298
0.73997548
0.73997854
0.73998977
0.73998112
0.73998263
0.73997477
0.73997529
0.73999009
0.7399824
0.74008994
0.74003253
0.7402447
0.73997668
0.74017278
0.73997055
0.74000908
0.73997871
0.74014231
0.74005099
0.73996981
0.73998965
0.74006329
Negative set
Positive set
Histogram of values distribution for the magnitude of enthalpy change
