Paper Citing NAMD - Abstract
Huang, Yulin; Rizzo, Robert C.
A Water-Based Mechanism of Specificity and Resistance for Lapatinib with ErbB Family Kinases
BIOCHEMISTRY, 51:2390-2406, MAR 27 2012
The dual kinase inhibitor lapatinib has a high affinity for EGFR and HER2 but a weak affinity for ErbB4, although the factors driving specificity for these highly homologous members of the ErbB family of receptor tyrosine kinases are not well understood. In this report, homology modeling, molecular dynamics simulations, and free energy calculations are employed with the goal of uncovering the energetic and structural molecular basis of lapatinib specificity and resistance. The results reveal a distinct network of three binding site water molecules that yield strikingly similar hydration patterns for EGFR and HER2 in contrast to that of ErbB4, which shows a different pattern with a reduced occupancy at one of the positions. The primary cause was traced to a single amino acid change in the binding site (EGFR position 775), involving a swap from C or S (EGFR and HER2) to V (ErbB4), for which the side chain is bulkier, is hydrophobic, and lacks the ability to form a H-bond with water. Notably, excellent quantitative agreement with experimental activities is obtained across the series (EGFR > HER2 > ErbB4) when key waters are included in the calculations. Quantitatively, Coulombic interactions and H-bond counts between network waters and species involved in the network are less favorable in ErbB4 by similar to 40% relative to those in EGFR or HER2. Additional simulations with clinically relevant EGFR (C775F, T854A, and T790M) and HER2 (T790I) mutants demonstrate that resistance can also be understood in terms of changes that occur in the binding site water network. Overall, the results of this study have yielded a physically reasonable water-based mechanism for describing lapatinib specificity and resistance.
