Calculated potentials of mean force between pseudo proteins.

<p>A: three PPs with varying net-charge, constant hydrophobicity and dipole moment; B: the two PPs with the largest and smallest hydrophobicities () but identical net-charges and dipole moments; C: six PPs with varying dipole moment, identical net-charge and similar values.</p

Effects of point directed mutagenesis on descriptors.

a<p>PDB ID.</p>b<p>Net-charge of wildtype (WT) in elementary charge units, e.</p>c<p>Net-charge, difference between mutant and WT.</p>d<p>Dipole moment of wildtype in eÅ.</p>e<p>Dipole moment, difference between mutant and WT.</p

Properties of pseudo proteins used in this study.

a<p>Net-charge in elementary charge units, e.</p>b<p>Dipole moment in eÅ.</p>c<p>first energy minimum in potential of mean force in kJ/mol.</p>d<p>Error bars from boot-strap analysis.</p

Correlations between the interaction strength and ΔG_min descriptors.

<p>A: the surface charge variation (SCV); B: a hydrophobicity descriptor (QH); C: the dipole moment p; D: the net-charge q.</p

Structure Based Descriptors for the Estimation of Colloidal Interactions and Protein Aggregation Propensities

<div><p>The control of protein aggregation is an important requirement in the development of bio-pharmaceutical formulations. Here a simple protein model is proposed that was used in molecular dynamics simulations to obtain a quantitative assessment of the relative contributions of proteins’ net-charges, dipole-moments, and the size of hydrophobic or charged surface patches to their colloidal interactions. The results demonstrate that the strength of these interactions correlate with net-charge and dipole moment. Variation of both these descriptors within ranges typical for globular proteins have a comparable effect. By comparison no clear trends can be observed upon varying the size of hydrophobic or charged patches while keeping the other parameters constant. The results are discussed in the context of experimental literature data on protein aggregation. They provide a clear guide line for the development of improved algorithms for the prediction of aggregation propensities.</p> </div

Two PPs with different surface topologies.

<p>Left: PP10, right: PP08. Atoms are colored according to the net-charges they carry (blue negative, red positive, white neutral). The PPs are oriented so that the atom with the maximum lssc value, the center of the patch with the highest hydrophobicity, is in the center of each representation.</p

Models for protein solubilities based on molecular descriptors.

<p>Results from three different linear regression models for protein solubilities, combining the protein net-charge (q) with one of the three descriptors dipole-moment (p), normalized SAP-score (nSAP), or largest SAP value (SAPmax), and from the CCSol web-server. Included are the coefficients of the linear regression models (Eq.3), the correlations between experimental and calculated solubility (), and the P-value (probability that the observed correlation is coincidental). Data are given for two protein sets: 18 proteins from EColi-K12 (setA), and 20 mutations of RNAseSA (setB).</p

Design, Synthesis, and Optimization of Novel Epoxide Incorporating Peptidomimetics as Selective Calpain Inhibitors

Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Cal1) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer’s disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Cal1. First generation analogues were potent inhibitors, effecting covalent modification of recombinant Cal1 catalytic domain (Cal1_cat), demonstrated using LC–MS/MS. Refinement yielded second generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Cal1 inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetics studies comparing full length Cal1 with the general cysteine protease papain