Kepp Research

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Protein mutation stability effects: SimBa

Mutations are central to protein evolution and can lead to disease or improved stability or function relevant
for developing better industrial enzymes. Most methods to estimate protein stability effects are complex (e.g. ML)
and trained on large data sets that we have shown carry substantial biases and hard to interpret and improve.

We have developed simple linear regression models (SimBa) that use only three properties of the mutation;
its change in hydrophobicity, its change in side chain volume, and the solvent exposure of the site.
These simple models enable physical interpretation while testing sensitivty effects to e.g. changing structures or data sets,
or fitting methods. One of the methods is best suited for natural mutations (SimBa-IB) and the other for situations where
 destabilizing andstabilizing mutations occur to similar extent (SimBa-SYM). Both are reported in the output of the method,
which is a pyhton script can can be downloaded and used for styding and further improvement at github:


https://github.com/kasperplaneta/SimBa2

O. Caldararu, T. L. Blundell, K. P. Kepp*, J. Chem. Inf. Model. 2021, 61, 4, 1981–1988,
"Three Simple Properties Explain Protein Stability Change upon Mutation"

K. T. Bæk, K. P. Kepp*, J. Comput. Chem. 2022, 43, 504-518,
"Data set and fitting dependencies when estimating protein mutant stability: Toward simple, balanced, and interpretable models"




OPLS force fields

Electrostatic interactions dominate proteins structure and dynamics. Yet anions and cations were not on the same
"free energy scale" in force fields. Thus, in 2006-2008 we developed OPLS force fields with consistent free energies
from experimental data for both +1 and -1 groups together (e.g. salt bridge dissocating during protein unfolding).

Non-bonded parameter files for Gromacs MD simulation:


OPLS-2006
Jensen, K. P. & Jorgensen, W. L. 2006

OPLS-2008/TIP4P
OPLS-2008/TIP3P
Jensen, K. P. 2008

Note that the protein force field OPLS-2008 depends on the water model.
The protein-water system cannot be separated.
TIP3P and TIP4P give very different charged solute hydration!

Our force fields are "water-optimized protein force fields" as important for charged groups.


More details can be found here.



Some research focus areas

Medicinal and Molecular Biochemistry
The zinc cascade of Alzheimer's Disease identifying new approaches and targets for treating the disease 

Alzheimer Theories


K. P. Kepp*, Chem. Rev. 2012, 112, 5193-5239: "Bioinorganic Chemistry of Alzheimer's Disease"
The "broad crossing mechanism" of oxygen binding and activation by heme, crucial to all life on this planet but formally forbidden by quantum mechanics (together with Ulf Ryde, Lund University) 

O2 binding

K. P. Kepp, Coordination Chemistry Reviews, 2017
"Heme: From quantum spin crossover to oxygen manager of life"

Presenilins:
The dynamic mechanism of presenilin, the main genetic risk factor of familial Alzheimer's disease





A. K. Somavarapu, K. P. Kepp*, Neurobiol. Disease 2016, 89, 147-156. "The dynamic mechanism of presenilin-1 function: Sensitive gate dynamics and loop unplugging control protein access"

A. K. Somavarapu, K. P. Kepp*, J. Neurochem. 2016, 137, 101-111. "Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer's Disease"
The loss of function theory of Alzheimer's disease



K. P. Kepp*, Progress in Neurobiology, 2016, 143, 36-60. "Alzheimer’s disease due to loss of function: A new synthesis of the available data"

N. Tang, K. P. Kepp*, J. Alzheimer's Dis. 2018, 66, 3, 939-945, "Aβ42/Aβ40 Ratios of Presenilin 1 Mutations Correlate with Clinical Onset of Alzheimer’s Disease"

K. P. Kepp*, J. Alzheimer's Dis., 2017, 55, 2, 447-457. "Ten Challenges of the Amyloid Hypothesis of Alzheimer's Disease"


Fundamental Physical Inorganic Chemistry

The thermochemcial spin series (complements the spectrochemical series of inorganic chemistry)




S. R. Mortensen, K. P. Kepp*, J. Phys. Chem. A 2015, 119, 4041-4050.

Oxophilicity and thiophilicity scale










K. P. Kepp*, Inorganic Chemistry, 2016, 55, 18, 9461-9470. "A Quantitative Scale of Oxophilicity and Thiophilicity"


K. P. Kepp*,
Transition Metals in Coordination Environments, 1-33 (2019), Springer. "The Electronic Determinants of Spin Crossover Described by Density Functional Theory"

M. T. Nielsen, K. A. Moltved, K. P. Kepp*, Inorg. Chem. 2018, 57, 7914-7924, "Electron Transfer of Hydrated Transition-Metal Ions and the Electronic State of Co3+ (aq)"


Density Functional Theory
Mapping the direction and magnitude of systematic effects in theoretical chemistry to obtain chemical accuracy
DFT use

K. P. Kepp*, Phys. Chem. Chem. Phys. 2018, 20, 7538-7548, "Energy vs. density on paths toward more exact density functionals"

K. P. Kepp*, Science, 2017, 356, 6337, 496-497. "Comment on “Density functional theory is straying from the path toward the exact functional”

K. P. Kepp*, Inorg. Chem. 2016, 55, 2717-2727. "Theoretical Study of Spin Crossover in 30 Iron Complexes"

K. A. Moltved, K. P. Kepp*, J. Chem. Theory Comput. 2018, 14, 3479–3492, "Chemical Bond Energies of 3d Transition MetalsStudied by Density Functional Theory"

O. S. Siig, K. P. Kepp*, J. Phys. Chem. A, 2018, 122, 4208–4217, "Fe(II) and Fe(III) Spin Crossover: Towards an Optimal Density Functional"