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Introduction
Heinrich does research in Biophysics, Computational Physics and Theoretical Physics, specifically in the fields of protein folding, misfolding and evolution. Before, he focused on theoretical membrane biophysics
Current institution
Additional affiliations
November 2014 - October 2016
October 2010 - November 2013
June 2005 - July 2006
Publications
Publications (66)
We compared the folding pathways of selected mutational variants of the α-spectrin SH3 domain (Spc-SH3) by using a continuum model that combines a full atomistic protein representation with the Gō potential. Experimental data show that the N47G mutant shows very little tendency to aggregate while the N47A and triple mutant D48G(2Y) are both amyloid...
Deciphering the effects of nonsynonymous mutations on protein structure is central to many areas of biomedical research and is of fundamental importance to the study of molecular evolution. Much of the investigation of protein evolution has focused on mutations that leave a protein's folded structure essentially unchanged. However, to evolve novel...
Stromal interaction molecule 1 (STIM1) resides in the endoplasmic reticulum (ER) membrane and senses luminal calcium (Ca²⁺) concentration. STIM1 activation involves a large‐scale conformational transition that exposes a STIM1 domain termed “CAD/SOAR”, ‐ which is required for activation of the calcium channel Orai. Under resting cell conditions, STI...
Stormorken syndrome is a multiorgan hereditary disease caused by dysfunction of the endoplasmic reticulum (ER) Ca2+ sensor protein STIM1, which forms the Ca2+ release-activated Ca2+ (CRAC) channel together with the plasma membrane channel Orai1. ER Ca2+ store depletion activates STIM1 by releasing the intramolecular "clamp" formed between the coile...
We present newly developed buffer systems that significantly improve the efficiency of a photochemically induced surface modification at the single molecule level. Buffers with paramagnetic cations and radical oxygen promoting species facilitate laser-assisted protein adsorption by photobleaching (LAPAP) of single fluorescently labelled oligonucleo...
The activation of the Ca²⁺-channel Orai1 via the physiological activator stromal interaction molecule 1 (STIM1) requires structural rearrangements within the entire channel complex involving a series of gating checkpoints. Focusing on the gating mechanism operating along the peripheral transmembrane domain (TM) 3/TM4-interface, we report here that...
The SecYEG translocon is a channel in bacteria, which provides a passage for secretory proteins across as well as integration of membrane proteins into the plasma membrane. The molecular mechanism, by which SecYEG manages protein transport while preventing water and ion leakage through the membrane, is still controversial. We employed molecular dyn...
The calcium release-activated calcium (CRAC) channel consists of STIM1, a Ca ²⁺ sensor in the endoplasmic reticulum (ER), and Orai1, the Ca ²⁺ ion channel in the plasma membrane. Ca ²⁺ store depletion triggers conformational changes and oligomerization of STIM1 proteins and their direct interaction with Orai1. Structural alterations include the tra...
The calcium release activated calcium channel is activated by the endoplasmic reticulum-resident calcium sensor protein STIM1. On activation, STIM1 C terminus changes from an inactive, tight to an active, extended conformation. A coiled-coil clamp involving the CC1 and CC3 domains is essential in controlling STIM1 activation, with CC1 as the key en...
Background
Every seventh diagnosis is a misdiagnosis. Each year, 1.5 million lives could be saved worldwide with the correct diagnosis. Physicians have to consider over 20,000 diseases. A study from Harvard University published in 2015 tested 19 symptom checkers and found them to be insufficient, with only 29–71% accuracy in diagnosis.
Objective
T...
Volumetric properties of proteins bear directly on their biological functions in hyperbaric environments and are useful in general as a biophysical probe. To gain insight into conformation-dependent protein volume, we developed an implicit-solvent atomic chain model that transparently embodies two physical origins of volume. First, a fundamental ge...
Sequence-dependent native preference ΔF(GA-GB) at the models’ respective Tms for four different SBM strengths εB.
Results for the ‒εB values tested are shown in different color as indicated, with εA = 0.96εB throughout. Negative or positive value along the vertical axis indicates how much the thermodynamic equilibrium is biased, respectively, towar...
Free energy landscapes of bi-stable sequences from constant-temperature simulations with a weak SBM potential.
Free energy as a function of QA and QB was simulated for GA98 (a) and GB98 (b) at each sequence’ respective Tm and εB = −0.25. For each sequence, 128 independent trajectories were simulated over 107 Monte Carlo cycles. The free energy for...
Contributions from different energy terms in the potential function for the hybrid model.
Shown here as examples are energies averaged over sampled GB98 conformations in the unfolded state (yellow columns) and in the GB-folded state (green columns) simulated using εB = −0.37. The unfolded state is defined by QA ≤ 0.6 and QB ≤ 0.3, the GB folded sta...
Free energy landscapes computed by simulations of GA98 and GB98 (a) using only the Lund potential without SBM, and (b) with all long-range interactions in the Lund potential turned off, but with the SBM on. In (a), the QA and QB reaction coordinates were based, respectively, on the 2LHC and 2LHD PDB structures. In (b), −εB was either 0.37 (top) or...
Free energy landscapes of bi-stable sequences from constant-temperature simulations.
Free energy as a function of QA and QB was simulated for GA98 (a) and GB98 (b) at each sequence’s respective Tm and εB = −0.37. For each sequence, 128 independent trajectories were simulated over 107 Monte Carlo cycles. The free energy for each sequence was compute...
Free energy landscapes computed using Hamiltonian replica exchange simulations of GA98 with varying −εB among replicas.
Simulations were conducted at the constant temperature shown at the top. The landscapes are depicted in the same style as that in S7 Fig.
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Mutation-induced population shift caused by L45Y from GA98 to GB98.
Clusters of conformations presented in Fig 4 of main text were further analyzed. The manner in which cluster size and structural elements are represented is the same as that in Fig 4 of main text. Number labels for select clusters are provided. Here “sequence bias” (vertical axis)...
Shift in unfolded-state contact frequencies caused by the L45Y mutation.
The unfolded state is defined by QA<0.6 and QB<0.3. The criterion for the residue-residue contacts considered here are the same as that for native contacts (Methods of main text). Contact order ≡ |i–j| + 1 for a contact between residues i and j. P(A) and P(B) are the fractions...
Difference landscapes for alternate switches.
(a) Free energy difference between GB98-T25I,L20A and GB98-T25I (former minus latter) as a function of QA and QB. It is known experimentally that GB98-T25I,L20A adopts the GB fold whereas GB98-T25I adopts the GA fold. (b) The corresponding free energy difference between the predicted switch sequences “S...
Effect of our model π-π interaction for F, Y on the GA/GB conformational switch.
Shown here are the QA/QB free energy landscapes of GA98 (a) and GB98 (b) in the modified hybrid model that incorporates the rudimentary π-π interaction defined in Methods of the main text in the model potential’s transferable component. Relative to the corresponding la...
Modeling details and related computational studies.
(PDF)
Multi-well Gaussian contact potentials for 95 consensus GA native contacts.
The contacts are numbered arbitrarily from 1 to 95. Residue pairs of the contacts are in parentheses. Here contact energy Eij (in units of ε) is a function of Cα-Cα distances rij (in Å). For each contact, a single Gaussian multi-well potential derived from the corresponding...
Effect of SBM strengths on simulated free energy landscapes in the hybrid model.
Free energy as function of QA and QB was computed using replica exchange for GA98 (left) and GB98 (right) for different ratios of SBM energies for GA and GB at the different models’ respective Tms, with εB = −1 throughout. (a,b) The GA and GB SBM basins have the same m...
Temperature replica exchange simulations of GA98 and GB98 under varying −εB, from 0.2 to 0.5.
QA vs QB free energy landscapes obtained after reweighting to the respective Tm. Simulation procedure and plotting style are the same as that described for Fig 3a of main text.
(TIFF)
Dependence of the native state preference ΔF(GA−GB) and melting temperature Tm (inset) on the SBM strength −εB for the simulations of GA98 and GB98 in S7 Fig.
Note that the GA fold is always favored more by GA98 than by GB98, whereas the GB fold is always favored more by GB98 than by GA98.
(TIFF)
Conformational diversity in putative transition-state ensembles.
Using the same conformational similarity measure for the k-means clustering of all accessible conformations (Methods of main text), a separate clustering of each of the three putative transition states, (a) TS-GA, (b) TS1-GB, and (c) TS2-GB, was performed for the (a) 453, (b) 834, and...
Multi-well Gaussian contact potentials for 137 consensus GB native contacts.
Same as S1 Fig but here the potentials were derived from the known folded structures of four GB sequences.
(TIFF)
Free energy landscapes computed using Hamiltonian replica exchange simulations of GB98 with varying −εB among replicas.
Simulations were conducted at the constant temperature shown at the top. The landscapes are depicted in the same style as that in S9 Fig.
(TIFF)
Transition fluxes among macroscopic states during Monte Carlo sampling.
For this analysis, conformations in the QA/QB energy landscapes are divided into three (a) or eight (b) macroscopic states. Transition frequencies between these states during Monte Carlo sampling were recorded. Normalized two-way transition frequencies shown here are for (c) GA...
This work investigates the role of N- to C- termini coupling in the folding transition of small, single domain proteins via extensive Monte Carlo simulations of both lattice and off-lattice models. The reported results provide compelling evidence that the existence of native interactions between the terminal regions of the polypeptide chain (i.e. t...
Author Summary
Dialysis-related amyloidosis (DRA) is a conformational disease that affects individuals undergoing long-term haemodialysis. In DRA the progressive accumulation of protein human β2-microglobulin (Hβ2m) in the osteoarticular system, followed by its assembly into amyloid fibrils, eventually leads to tissue erosion and destruction. Discl...
One of the major components of amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of protein β2-microglubulin (hβ2m), ΔN6, which lacks six N-terminal residues. In vitro experiments showed that contrary to the wild-type form, ΔN6 is able to form amyloid fibrils at physiological pH. Furthermore, a mild acidificat...
We performed extensive lattice Monte Carlo simulations of ribosome-bound stalled nascent chains (RNCs) to explore the relative roles of native topology and non-native interactions in co-translational folding of small proteins.We found that the formation of a substantial part of the native structure generally occurs towards the end of protein synthe...
We assessed the interplay of native topology and non-native interactions on surface-tethered protein folding via extensive Monte Carlo simulations of a simple lattice model. In particular, we investigated the thermodynamics and kinetics of protein-like sequences enclosing different amounts of non-native interactions to protein energetics, and which...
Gō models are exceedingly popular tools in computer simulations of protein folding. These models are native-centric, i.e., they are directly constructed from the protein's native structure. Therefore, it is important to understand up to which extent the atomistic details of the native structure dictate the folding behavior exhibited by Gō models. H...
Dimensional analysis.
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Free energy of a membrane in a single-well potential.
(PDF)
Submicron scale domains of membrane-anchored receptors play an important role in cell signaling. Central questions concern the stability of these microdomains, and the mechanisms leading to the domain formation. In immune-cell adhesion zones, microdomains of short receptor-ligand complexes form next to domains of significantly longer receptor-ligan...
![Fig. 3 Concentrations [RL] and [R] of bound and unbound receptors as a...](profile/Heinrich-Krobath/publication/45855807/figure/fig2/AS:349279651680275@1460286166720/Concentrations-RL-and-R-of-bound-and-unbound-receptors-as-a-function-of-the-receptor_Q320.jpg)
Cell membranes interact via anchored receptor and ligand molecules. Central questions on cell adhesion concern the binding affinity of these membrane-anchored molecules, the mechanisms leading to the receptor-ligand domains observed during adhesion, and the role of cytoskeletal and other active processes. In this review, these questions are address...
The adhesion of cells is mediated by receptors and ligands anchored in apposing membranes. A central question is how to characterize the binding affinity of these membrane-anchored molecules. For soluble molecules, the binding affinity is typically quantified by the binding equilibrium constant K3D in the linear relation [RL] = K3D [R][L] between t...
The adhesion of cells is mediated by membrane receptors that bind to complementary ligands in apposing cell membranes. It is generally assumed that the lateral diffusion of mobile receptor-ligand bonds in membrane-membrane adhesion zones is slower than the diffusion of unbound receptors and ligands. We find that this slowing down is not only caused...
