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Computational Research in Molecular Chemistry
Integrating comparative modeling and accelerated simulations reveals conformational and energetic basis of actomyosin force generation.Ma, Y., S. You, M. Regnier, J.A. McCammonProc. Natl. Acad. Sci. USA in press.    
Muscle contraction is performed by arrays of contractile proteins in the sarcomere. Serious heart diseases, such as cardiomyopathy, can often be results of mutations in myosin and actin. Direct characterization of how small changes in the myosin-actin complex impact its force production remains challenging. Molecular dynamics (MD) simulations, although capable of studying protein structurefunction relationships, are limited owing to the slow timescale of the myosin cycle as well as a lack of various intermediate structures for the actomyosin complex. Here, employing comparative modeling and enhanced sampling MD simulations, we show how the human cardiac myosin generates force during the mechanochemical cycle. Initial conformational ensembles for different myosin-actin states are learned from multiple structural templates with Rosetta. This enables us to efficiently sample the energy landscape of the system using Gaussian accelerated MD. Key myosin loop residues, whose substitutions are related to cardiomyopathy, are identified to form stable or metastable interactions with the actin surface. We find that the actin-binding cleft closure is allosterically coupled to the myosin core transitions and ATP-hydrolysis product release from the active site. Furthermore, a gate between switch I and switch II is suggested to control phosphate release at the pre-powerstroke state. Our approach demonstrates the ability to link sequence and structural information to motor functions.
Editorial: Mechanisms, thermodynamics and kinetics of ligand binding revealed from molecular simulations and machine learningMiao, Y., C.A. Chang, W. Zhu, J.A. McCammonFront. Molec. Biosci. In press (2023).    
PERIOD phosphorylation leads to feedback inhibition of CK1 activity to control circadian period.Philpott, J.M., A.M. Freeberg, J. Park, K. Lee, C.G. Ricci, S.R. Hunt, R. Narasimamurthy, D.H. Segal, R. Robles, Y. Cai, S. Tripathi, J.A. McCammon, D.M. Virshup, J.C. Chiu, C. Lee, C.L. Partch.Molecular Cell, in press (2023).    
Capturing differences in the regulation of LRRK2 dynamics and conformational states by small molecule kinase inhibitors.Weng, J.-H., W. Ma, J. Wu, P. Kaila Sharma, S. Silletti, J.A. McCammon, S. Taylor.ACS Chem. Biol. In press (202).    
Mutations in the human leucine rich repeat protein kinase-2 (LRRK2) create risk factors for Parkinson’s disease, and pathological functions of LRRK2 are often correlated with aberrant kinase activity. Past research has focused on developing selective LRRK2 kinase inhibitors. In this study, we combined enhanced sampling simulations with HDX-MS to characterize the inhibitor-induced dynamic changes and the allosteric communications within the C-terminal domains of LRRK2, LRRK2RCKW. We find that the binding of MLi-2 (a type I kinase inhibitor) stabilizes a closed kinase conformation and reduces the global dynamics of LRRK2RCKW, leading to a more compact LRRK2RCKW structure. In contrast, the binding of Rebastinib (a type II kinase inhibitor) stabilizes an open kinase conformation, which promotes a more extended LRRK2RCKW structure. By probing the distinct effects of the type I and type II inhibitors, key interdomain interactions are found to regulate the communication between the kinase domain and the GTPase domain. The intermediate states revealed in our simulations facilitate the efforts toward in silico design of allosteric modulators that control LRRK2 conformations and potentially mediate the oligomeric states of LRRK2 and its interactions with other proteins.
Multiscale Computational Modeling of the Effects of 2-deoxy-ATP on Cardiac Muscle Calcium HandlingHock, M.T., A.E. Teitgen, K.J. McCabe, S.P. Hirakis, G.A. Huber, M. Regnier, R.E. Amaro, J.A. McCammon, A.D. McCulloch.Journal of Applied Physics, in press (2023).    
Interface Engineering of Carrier Protein–Dependent Metabolic PathwaySztain, T., J.C. Corpuz, T. Bartholow, J. Sanlley, Z. Jiang, D. Mellor, G.W. Heberling, J. LaClair, J.A. McCammon, M.D. BurkartACS Chemical Biology in press (2023).    
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