Factors Promoting the Formation of Clathrate-Like Ordering of Water in Biomolecular Structure at Ambient Temperature and Pressure Sridip Parui and Biman Jana* School of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India ABSTRACT: Clathrate hydrate forms when a hydrophobic molecule is entrapped inside a water cage or cavity. Although biomolecular structures also have hydrophobic patches, clathrate-like water is found in only a limited number of biomolecules. Also, while clathrate hydrates form at low temperature and moderately higher pressure, clathrate-like water is observed in biomolecular structure at ambient temperature and pressure. These indicate presence of other factors along with hydrophobic environment behind the formation of clathrate-like water in biomolecules. In the current study, we presented a systematic approach to explore the factors behind the formation of clathrate-like water in biomolecules by means of molecular dynamics simulation of a model protein, maxi, which is a naturally occurring nanopore and has clathrate-like water inside the pore. Removal of either confinement or hydrophobic environment results in the disappearance of clathrate-like water ordering, indicating a coupled role of these two factors. Apart from these two factors, clathrate-like water ordering also requires anchoring groups that can stabilize the clathrate-like water through hydrogen bonding. Our results uncover crucial factors for the stabilization of clathrate-like ordering in biomolecular structure which can be used for the development of new biomolecular structure promoting clathrate formation. ■ INTRODUCTION Clathrate compounds are usually a binary mixture of two substances where a guest molecule is trapped inside the cage or lattice of host molecule. 1,2 Substances like H 2 O, SiO 2, Si, Ge, etc., which are able to form tetrahedral network in their pure crystal, can also make clathrate structures in the presence of a suitable guest molecule. 3 These substances are connected with each other and form a lattice-like structure with polyhedral cages with an appropriate cavity inside which a guest solute can fit. A unique feature present in these clathrates is that the guest molecules hardly interact with each other while strong interaction is found among host molecules in the tetrahedral lattice. Clathrate hydrate is a crystalline solid of water in which nonpolar molecule, usually gas molecule, is trapped inside the cages of hydrogen-bonded water molecules. Large amounts of natural gases are reserved on the ocean floor in the form of clathrate hydrate. 4−6 Because of many practical purposes and applications, 4,7−10 thermodynamics and kinetics of clathrate hydrate in the context of its growth, 11−14 promotion, 15−17 and inhibition 18−22 have become a fascinating topic in the field of physical chemistry. Formation (or decomposition) of clathrate hydrate is a first order phase transition. Though there are several proposed mechanisms for nucleation pathways for the formation of clathrate hydrate, 11−14 it is still an active field of research. 23 Clathrate hydrates are formed at suitable temper- ature and pressure (typically at cold temperature and moderately high pressure). In general, guest molecules are needed to stabilize the clathrate. However, guest-free clathrate has been synthesized for Ge 24 and Si. 25 The synthesis of an empty clathrate is yet to be realized in laboratory. There were some computational efforts to make a guest-free clathrate of water. 26,27 Molinero and co-worker showed that empty clathrate of water can form but at high negative pressure. 26 Bai et al. reported an evidence of formation of guest-free clathrate inside a hydrophobic-slit but at a temperature below the melting temperature of used water model TIP5P. 2827 So, an empty clathrate at ambient temperature and pressure is unstable and difficult to detect or synthesize. Buchanan et al. did not observe significant changes in water structure before clathrate hydrate formation and after clathrate hydrate decomposition denying the clear support of the memory effect. 29−3132 This indicates that, in absence of guest molecule, clathrate cages would collapse at positive pressure. Interstitial guest molecules thus stabilize the clathrate cages by preventing the collapse of the clathrate cavity. Unlike ice hexagons, clathrate hydrates are largely composed of poly pentagonal rings. Structure of water in clathrate hydrate Received: November 19, 2018 Revised: January 3, 2019 Published: January 3, 2019 Article pubs.acs.org/JPCB Cite This: J. Phys. Chem. B XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.jpcb.8b11172 J. Phys. Chem. B XXXX, XXX, XXX−XXX Downloaded via INDIAN ASSOCIATION CULTIVATION SCI on January 29, 2019 at 06:02:29 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.