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Kasper Planeta Kepp

Research interests:
Fundamental physical and inorganic chemistry:
Laws of thermodynamics and quantum mechanics applied to chemical problems of importance.

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.


RECENT DISCOVERIES IN PROTEIN MISFOLDING DISEASES:

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.

 

 

 

 

 

Contact

Kasper Planeta Kepp
Professor
DTU Chemistry
+45 45 25 24 09
MIND
MIND - Metalloproteins In Neurological Disorders - an interdisciplinary network