Kepp Research

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Research interests and some accomplishments:

Fundamental physical and inorganic chemistry: Laws of thermodynamics and quantum mechanics applied to chemical problems of importance. For example, the first scale of oxophilicity (2016)
Explaining the interplay of entropy and enthalpy in spin crossover (2012-2016).

Protein science and theoretical biochemistry: The structure, dynamics, function, and natural evolution of proteins.

Applications:  To identify the molecular causes of neurological diseases such as Alzheimer's Disease and ALS, to define new therapeutic strategies, and use "rational evolution" to invent new efficient enzymes for industrial purposes.


2016: The Loss of Function theory of Alzheimer's Disease.

2016: The gate-plug mechanism whereby mutations in presenilin 1 cause Alzheimer's Disease: Loss of hydrophobic packing and stability in the membrane reduces cleavage accuracy and function. The properties can be correlated directly to clinical severity of PSEN1 variants.

2016: Protein stability effects are universal and can predict stabilities of protein variants relevant to protein engineering and evolution.

2015: The structure of β-amyloid in best agreement with available experimental data, from comparison of 21 force field methods.

2015: The Energy Theory of Neurodegeneration. Neurodegeneration in ALS can be shown to be due, not to a specific toxic molecular mdoe of protein aggregation but to systemic energy burden of protein turonover. This increased energy cost correlates directly with patient data and explain many features of ALS not previously explained, including why protein misfolding causes disease specifically in neurons, the most energy-demanding cells of the body.

2015: The molecular features of  β-amyloid that cause toxicity. Specific conformational features and exposed parts of the peptides explain the experimental toxicities of different peptide variants. These features can now be targeted by molecular intervention.

MAIN EARLY DISCOVERIES 2003-2009 (all as first author):

2003: Explaining molecular co-evolution of metal ions and tetrapyrrole cofactors from thermodynamic stability and function (with U. Ryde).

2004: The broad crossing mechanism of ligand binding to heme, explaining how molecular evolution of close-lying spin states in heme allows fast reversible binding of dioxygen crucial to life (with U. Ryde).

2005: O2 binding to heme is the basis of higher life forms on this planet, but the process has been debated for 50 years. We did the first high-level calculation of this problem (multistate CASPT2), to answer the old question about the relative contributions of Pauling, Weiss, and Goddard / McClure resonance forms (with Björn Roos & Ulf Ryde).

2005: Our mechanism of how the Co-C bond is cleaved in B12-dependent enzymes. QM/MM simulations show that the Ado radical is stabilized by electrostatic interactions and the Co(III) ground state is distorted. Both effects (product stabilization and reactant destabilization) contribute (with U. Ryde).

2006: OPLS-2006 force field: First co-parameterization of anions and cations of salts for use in molecular simulation, to make free-energy consistent salt solutions critical to molecular simulation (with W. L. Jorgensen).

2008: OPLS-2008 force field: First demonstration of the water model --- protein force field interdependence that affects most protein simulations and two specifically parametrized OPLS force fields for charged residues, one for TIP3P water and one for TIP4P water.

2008-2009: It was shown by benchmarking against various experimental data that the density functional method TPSSh by Tao, Perdew, and co-workers, is a very accurate functional for inorganic chemistry vs. normally used functionals.

June 2018: Welcome to Budheswar, who will work as a postdoc on predicting Alzheimer's disease-causing mutations
May 2018: Humble thanks to DFF and the Danish taxpayers for supporting our project on developing new protein stability prediction tools
May 2018: Kasper silently celebrates his 100th review report for ACS in the Paragon Plus System.
April-May 2018: Kasper is on family leave from work.
Feb 1, 2018. Ning Tang joins as DFF postdoctoral fellow working on new medicine targeting gamma secretase in Alzheimer's disease. Welcome!
Jan 1, 2018. Rukmankesh will join our group to study laccases in collaboration with Prof. Anne Meyer, DTU Chemical Engineering - Welcome!
Dec 12, 2017. Arun defends his ph.d. thesis on proteins in Alzheimer's Disease. Congratulations!
Dec 7, 2017. NNF awards us funding for our project that will explore the causes and disease properties of mutations in Alzheimer's disease. Thanks!
July 4, 2017. Kasper speaks at the EICC4 conference
May 8, 2017. Kasper will speak at the Danish Annual meeting for Neuroscience
May 8, 2017. DFF funds our research into the mechanism and new treatments targeting the protein gamma secretase (commence 2018) Thanks!
March 2017. Review of heme's amazing chemical properties and role in life is out.
Feb 2017. Benchmarking DFT for gold: First detailed benchmark of DFT's ability to describe diverse chemical bonds to gold
Jul 2016. Kasper speaks at the ICPP conference in Nanjing, China, on heme biochemistry.
Jun 2016. Loss of function in Alzheimer's Disease. A comprehensive explanation why current clinical trials fail
Apr 2016. Protein stability effects are universal and can predict stabilities of protein variants relevant to protein engineering and evolution. 
Feb 2016. The general mess of Aβ. New meta-analysis shows no relationship between cell and mouse data and clinical outcome, i.e. do not reflect aging human AD.
Sep 2015. The quest for the structure of β-amyloid (new work published in ChemPhysChem)
Aug 2015. Speaking at the ECOSTBio meeting in Belgrade, Aug 24-25.
July 2015. Speaking at the ICCB conference in Kauai, Hawaii, July 2 to 6. 
June 2015. EMBO neuro- degeneration meeting in Heidelberg June 14-17. 
March 2015. Molecular Causes of ALS: Coupling protein energy to real patient data. 
Feb 2015. New mechanism of laccase inhibition: impairing reorganization energies. 
Nov 2014. New patent WO2014167112 for synthesizing sugars 
Nov 2014. First relation between patient data and chemical properties of genetic variants causing Alzheimer's disease
Oct 2014. Søren Brander defends his Ph.D.  Congratulations!
Sep 2014. Arun joins our group as a ph.d. student to work on proteins involved in Alzheimer's disease.
Dec 2013. Kasper joins the Management commitee of the COST action on spin states in biochemistry and technology

Jun 2013. Pouria Dasmeh successfully defends his Ph.D. Congratulations!
Dec 2012. Our research is described in the Danish newspaper Politiken.
Oct 2012. New review in Chemical Reviews on "Bioinorganic Chemistry of Alzheimer's Disease"
Sep 2012. Kasper speaks at the CECAM workshop in Zaragoza, Sep 18-21.
Aug 2012. New review on "Consistent descriptions of metal–ligand bonds and spin-crossover in inorganic chemistry"

Copyright 2014. Kasper P. Kepp.

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